Inhibition Of The 5 Lipoxygenase Pathway Biology Essay

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To review the concerns in the last 5 years for the diagnosis of asthma and to assess the efficacy of treatments such as omalizumab, disodium cromoglycate and leukotriene antagonists to help relieve symptoms of acute and chronic asthma.

Background: Asthma is a condition that affects the airways. It is where the airways constrict and this makes breathing more difficult. Typical symptoms are coughing, wheezing, chest tightness and shortness of breath. The condition causes inflammation and swelling of the airways of the bronchi. If you have asthma the bronchi become sensitive than usual and certain substances can irritate them more easily. Asthma is a chronic disease that affects children in economically developed countries; the condition is also common in adults. It is increasing in severity and prevalence.

Method: Scientific online journal sites such as PubMed, Science Direct and Medline were searched using the following keywords: omalizumab, disodium cromoglycate and leukotriene antagonists in order to select relevant for the write up of the report. A variety of studies were chosen in order to analyse the data and reach to an ethical conclusion.

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Results/Discussion: The studies that had been reviewed had found that omalizumab has been shown to decrease the incidence of asthma exacerbations in these patients and helps relieve symptoms for patients suffering from severe allergic asthma. Studies also found that disodium cromoglycate helps relieve asthma symptoms when it is used at an early stage of the condition. Also leukotriene antagonists were found not to have the desired effect as previously thought however they do stop the symptoms of the condition.

Conclusion: The drugs discussed within this report all help patients with asthma the treatment of bronchial asthma is 2010 is still awaiting the optimal and safe therapeutic effect.

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Introduction

There are a number of definitions of asthma in the literature, one of which states that the disease is "An acute respiratory disorder characterised by unusually reactive, constricting airways" (1). Asthma is a chronic condition that affects the airways. Although usually asthma is thought to be a chronic condition in reality it can take both acute and chronic forms. Whatever the time scale it does affect the airways and the resulting problems cause symptoms such as wheeze and chest tightness. Overall the condition may be characterised by variable and widespread airflow obstruction.

The typical symptoms of asthma are coughing, wheezing, chest tightness and shortness of breath (2). The condition causes local inflammation due to the local release of inflammatory mediators of these can cause local oedema bronchoconstriction and so tissue stretching which limits air flow in the bronchial airways (3). Common triggers of the condition are tobacco smoke, dust mites, pollen and cold air and this range of stimuli clearly show that one factor is not responsible for all cases of asthma.

Classification of asthma can simply be made into two categories, either extrinsic or intrinsic. Extrinsic asthma is caused by the type of immune system response to inhaled allergens such as pollen, animal dander or dust mite particles, which is the classical hypersensitivity type 1 reaction (2). People suffering Atopic asthma or as its known more commonly as extrinsic asthma, usually have other allergy related problems such as hay fever, eczema and rhinitis. Atopic asthma suffers usually respond well to inhaled steroids as they suppress the immune system (3). Intrinsic asthma on the other hand is non-allergy related, it is triggered by tobacco smoke and stress. However the treatment is more complicated so simply avoiding triggers is not as easy.

The onset of asthma can occur at two different stages, childhood and adulthood. If the onset of asthma begins in childhood it is often associated with atopy, which is the genetic susceptibility to produce IgE to common environmental allergens (4). A cell which is central to the problem of extrinsic asthma is the mast cell. This cell is rather unusual since it possesses membrane receptors which bind immunoglobulin E. Once attached these immunoglobulins remain and when they come in contact with the allergen (airborne antigen) an antigen, antibody response occurs which releases the intracellular grammar some of which cause bronchi constriction. Wheezing occurs during a viral infection in childhood, a family history of allergies is strongly associated with recurrent asthma throughout childhood (4). Commonly identified in children, it can also occur later in life. Adult-onset asthma also associated with atopy. Some adults develop asthma without IgE antibodies to allergens. These adults often suffer from coexisting sinusitis, nasal polyps and aspirin or NSAID allergies. Occupational exposures to materials such as, animal products, wood dusts and biological enzymes can also cause asthma (5).

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When air enters the lung under normal conditions, the thorax expands due to a pressure decrease in the thoracic cavity. The pressure decreases due to the descent of the diaphragm and the upward movement of the rib cage. The pleura are a layer of membrane surrounding each lung separately. When the chest expands, there is a pull force on the pleura, as the pleura cannot be separated from the lung. Due to this reason, the lung expands filling with air. In expiration, the passive of the structures in the lung, cause a decrease in the size of the chest, allowing the diaphragm to relax. This recoil makes expiration a passive process in contrast to the active process of inspiration (6).

Figure 1: Diagram representing the onset of asthma showing the different pathways of how shortness of breath is induced.

In asthma which is usually a reversible airway disease in addition to the bronchoconstriction effect is usually characterized by over developed mucus gland. These glands produce an excess of mucus which has also an increased viscosity which makes its clearance by the cilia involved in the mucociliary escalator more difficult than normal (7). Consequently the mucus is retained and effectively reduces airway diameters so compromising air flow and so respiratory gas exchange, the mucus which causes a thick layer to form hence reducing the size. Inflammation often occurs due to release of anti inflammatory mediators, and form cells involved in the immune response such as lymphocytes and especially in the lung, cosmophils due to immune response. Bronchconstriction causes narrowing of airway muscle, due to stimulation of smooth muscle (8). During an asthma attack the lungs expand because there is a large amount of air trapped within them. As a result of this the proprioceptors in the pleurae stretch effectively and this may cause pain (2).

There are many drugs on the market to help relive asthma suffers of their symptoms. The principle aims of the pharmacological treatment of the disease are threefold. Firstly to control the symptoms, including nocturnal symptoms, secondly prevent of exacerbations and thirdly to achieve of the best possible pulmonary function with minimal side effects.

There are many drug strategies in the treatment of asthma. This dissertation will focus on 3 of them namely, immunoglobulin E antagonists (omalizumab), disodium cromoglycate and leukotriene antagonists. First of all the Omalizumab is a humanised antibody drug approved for patients with moderate-to-severe or severe allergic asthma (11), which is caused by hypersensitivity reactions to certain environmental substances. The cost of the drug is high (annual cost for England and Wales could be between £2.6 million and £7.1 million). Omalizumab is prescribed mainly for patients with severe persistent asthma, which cannot be controlled with high doses of corticosteroids. Omalizumab may potentially cause anaphylaxis (a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000 (12).

Novel treatment options have focussed on a group of patients who cannot obtain symptom control using currently available treatments. A subgroup of these patients will have allergic type asthma and produce excess IgE in response to allergens. Exposure to the allergen leads to initiation of an inflammatory response and subsequent bronchoconstriction. The prevalence of asthmatic patients who have an allergic component to their disease is usually less than 50%. Antibodies to IgE can reduce the allergen response by binding with free IgE preventing its involvement in this part of the inflammatory cascade. http://www.nyrdtc.nhs.uk/docs/eva/Omalizumab.pdf

Disodium cromoglycate is known as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate. This drug prevents the release of inflammatory chemicals such as histamine from mast cells (requires administration four times daily, and does not provide additive benefit in combination with inhaled corticosteroids) (13).

Leukotrienes are synthesised from arachidonic acid, a normal constituent of the phospholipid bilayer which is liberated by the action of phopholipases in response to various stimuli.

Leukotrienes are naturally produced eicosonoid lipid mediators. They are considered to have roles in both autocrine signalling and paracrine signalling as in to regulate the body`s response (9). Leukotrienes are produced from arachidonic acid by the enzyme 5-lipoxygenase in the body. These agents are not stored inside a cell but are always made "de novo", on demand and then they exert their physiological effects.

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Leukotriene antagonist (sometimes referred to as a leukast) is a drug that blocks the receptors since it can classed as a "receptor antagonist" leukotrienes, are "fatty compounds" which are produced by the cells in immune system that cause inflammation in asthma and bronchitis, and constrict airways. Montelukast, zafirlukast and zileuton, are all leukotriene antagonists which are used to treat those diseases because of their perceived safety. Leukotriene receptor antagonists have largely replaced sodium cromoglycate as the non-corticosteroid treatment of choice (10).

Asthma is controlled using a step-wise approach which relies on symptom severity as a guide to treatment options. Patients with severe asthma are likely to be treated with regular high-dose corticosteroids (inhaled or oral), inhaled B2 agonists and standard adjunctive treatment (e.g. leukotriene receptor antagonists, sustained release theophylline or B2 agonist tablet).

Current asthma treatments act directly on smooth muscle to cause bronchodilation (B2 agonists, theophylline) or by interfering with the inflammatory process (inhaled corticosteroids - ICS). As doses of ICS rise, consideration of the risk and implications of associated side-effects becomes important, especially with long-term use.

There are many concerns with regards to the diagnosis of asthma, nowadays doctors are quick to diagnose children without going through the necessary procedures and looking at the symptoms before diagnosing a child. Parents would bring their children to the surgery with a cold or an infection of both breathing difficulties is a symptom, doctors would be too quick to diagnose it as asthma. However the over diagnosis does not just refer to children it also applies to obese and smokers. Chirag et al carried out a study in relation to the over diagnosis of asthma and its relationship to BMI, they found that doctors over diagnosed asthma upon those who were clinically obese.

Aims

The aim of my study was to examine the reason for the diagnosis of asthma and the different types of treatments that have been available to treat the symptoms in the last 5 years. Which different types of treatments are available for asthma and what future treatments are going to become available?

It will briefly discuss what the major causes of asthma are and the reason why these causes arise. The difference between the severity of asthma and the different treatments available and how this differs with age will also be studied.

The report will look into what the major causes of asthma are; the diagnosis and the different types of treatments that are available and the future treatments that are going to be available.

Along with the causes of asthma the treatments of the condition will also examined and critically analysed. These have been discussed in the introduction and will be investigated further. Future treatments for the condition will also be examined and critically analysed. The main aim of the report will be to find out if the treatments available for asthma relieve the symptoms and reduce the causes. If the aim is met further study can be carried out researching whether treatments improve mental symptoms.

Methods

Previous investigations that have been conducted in this area will be analysed alongside the information relating to asthma; such as both causes and treatments of the condition. The data generated will be used to see what asthma is diagnosed and the treatments that are available.

Information collected from various published medical journals, will be checked for relevance in relation to the study in hand. Only the most recent journals will be used providing up to date information. On line electronic journals will be used from Pub Med, science direct and other journal sites.

Diagnosis of asthma and treatments have been a common topic in the media, as more research has been carried out and ore specialists have been involved. Hence, articles from the media will be used, as they contain highly specialised knowledge, facts, and opinions.

Statistical tests will be considered, a contrast will be made of the different types of causes of asthma, which cause is the most common of effecting asthma and which treatment is the most effective in relieving the symptoms. The statistical tests that will be used will be decided upon the relevance of the data.

Books are also a useful resource for this study as they will help provide back ground information on asthma, the causes of the condition and the different types of treatments available.

Discussion

This dissertation aims to focus on the recent developments in drugs to treat bronchial asthma. If the reader would like to fully understand the treatments prior to 2005 the review by Effros and Nagaraj (3) and clearly describes and considers the situation at this date. To consider more recent therefore this discussion will primarily be divided into three sections, namely considerations of omalizumab, disodium cromoglycate and leukotriene antagonists.

Omalizumab is a recombinant DNA derived humanized IgG1K monoclonal antibody that binds to human immunoglobulin E (IgE) (REFERENCE). IgE is commonly associated with allergies when present in high amounts within the body.

Omalizumab (Xolair) is a recombinant humanised monoclonal antibody that inhibits the binding of IgE to high affinity receptors (FcεRI) on the surface of mast cells and basophils (REFERENCE). It prevents the release of pro-inflammatory mediators and reduces allergen-induced airway reactions. Omalizumab is licensed as add-on therapy in order to improve asthma control in both adults and adolescents with severe persistent allergic asthma. It is also licensed for those who have a positive skin test to a perennial aeroallergen and who have reduced lung function (forced expiratory volume in 1 second, FEV1 < 80% )along with recurrent daytime symptoms or night-time awakenings and who have had multiple documented severe exacerbations despite the daily high-dose inhaled corticosteroids, in addition to a long-acting inhaled beta-2 agonist. The approved indication states that omalizumab treatment should be considered for patients with convincing IgE mediated asthma only. http://www.nice.org.uk/nicemedia/live/11894/38392/38392.pdf.

Omalizumab is prescribed for patients with severe persistent asthma, which cannot be controlled with high doses of corticosteroids. Specialists who are experienced within the field of diagnosis and treatment of severe asthma should initiate treatment with omalizumab. If the treatment is to continue long-term then responsibility should be transferred to primary care, shared care arrangements need to be implemented. The dose prescribed depends on baseline IgE levels and on patient weight. Doses range from 75mg every four weeks to 375mg every two weeks, annual costs per patient will therefore be between £3,074 and £18,444. Annual cost for an average 70kg patient with serum IgE of 200-300IU/ml would be £12,000. http://www.nyrdtc.nhs.uk/docs/eva/Omalizumab.pdf.

Omalizumab is not licensed for children under the age of 12, even though patients from 6 years and over were included within a number of initial trial populations. On-going efficacy and safety studies involving children within this age group are being carried out and this may be an area for future license extension.

There have also been studies done to evaluate the effect of omalizumab on symptom control, in patients with allergic rhinitis, a condition for which the drug is licensed in the United States. http://www.nyrdtc.nhs.uk/docs/eva/Omalizumab.pdf.

Figure 2: Diagram representing Omalizumab binding to IgE, preventing mast cell activation. (source: http://www.clinicalpharmacy.org.uk/May/Omalizumab.pdf)

Omalizumab is used for patients with severe persistent allergic asthma. The therapeutic efficacy is more evident among strong severe patients are 60-80%. 30-40% of adult asthma causes are not to allergy and unresponsive to omalizumab. Within its licensed indication, omalizumab is recommended for the treatment of severe allergic asthma (IgE mediated) as add-on therapy to optimised standard therapy, for adults and adolescents who are identified as having the severe condition. http://guidance.nice.org.uk/TA133/Guidance.

Omalizumab add-on therapy is only to be initiated if the patient meets the following criteria of severe allergic asthma;

Confirmation of IgE mediated allergy to a perennial allergen by clinical history and allergy skin testing.

Two or more severe exacerbations of asthma which required hospital admission within the previous year, or three or more severe exacerbations of asthma within the previous year, at least one of which required admission to

hospital, and a further two which required treatment or monitoring in excess of the patient's usual regimen, in an accident and emergency unit. http://www.nice.org.uk/nicemedia/live/11894/38392/38392.pdf.

Common side effects associated with omalizumab treatment include bruising, erythema and pain at the site of injection. Rare side effects include anaphylaxis and increased risk of parasitic infections, these usually occur with the first 2 hours of the injection and possible drug-induced malignancies. Prescribed information has been revised based on post examination that indicates that allergic reactions such as anaphylaxis and anaphylactic shock may occur after 2 hours and occasionally 24 hours after the injection. Patients are to be informed that such reactions may occur and should seek medical attention if these reactions occur.

Availability of omalizumab for children from the age 6 to 11 years provides an extra treatment choice for patients who have exhausted other forms of therapy. Omalizumab was very effective in decreasing asthma exacerbations as an adjunctive therapy to inhaled steroids, and also during tapering phases of clinical trials. Although there were more injection site reactions omalizumab was well tolerated. Patient and physician assessments of the drug were positive (15).

The cost of omalizumab will varies depending on the dose required. A 150mg vial costs £256, so the total cost of therapy for a patient receiving 75mg every four weeks would be £3,328 per annum, and a schedule of 375mg every two weeks would be £19,968 per annum (reference). Nursing administration times also need to be taken into account (vials take at least 20 minutes to reconstitute), plus any required assessments and monitoring.

Pharmacists and any other staff involved in administering omalizumab should be aware of the allergic reactions associated of the drug, (including anaphylaxis and anaphylactic shock). These reactions are uncommon (an incidence of less than 1 in 1,000), however may occur within 2 hours of administration, although they can sometimes occur more than 24 hours later.

Treatment for the anaphylactic reactions (e.g. an adrenaline auto-injector [EpiPen]) is always to be made available following the administration of the drug should any complications arise. Patients should be made aware of the reactions and the signs and symptoms of such reactions, and should take seek medical attention if the reactions do occur. http://www.clinicalpharmacy.org.uk/May/Omalizumab.pdf.

Disodium cromoglycate is the sodium salt of 1,3-bis-(2carboxychromon-5-yloxy)-2-hydroxypropane. The mode of action of this drug has been related to Cox 2, and it is now being studied in patients with airway disease.

There are of course differences of detail between the different species of the drug disodium cromoglycate, but the principal effect of it is to inhibit the degranulation of sensitized mast cells which otherwise occurs after a challenge by antigen. The release of pharmacologically active substances including histamine and 5-hydroxytryptamine and substances which may induce anaphylaxis, is caused by the interaction of the antigen with the cell bound antibody.

Cromoglycate inhibition is not specific to mast cells sensitized by heat-labile reagin (IgE), but it is also effective when the antibody is heat-stable IgGa and in other systems. The inhibition in release of spasmogens by apparently stabilizing the mast cell membrane, only occurs if the antigen -antibody reaction combination takes place, and only if it takes place before the reaction has started. This occurs without affecting the fixation of the reaginic antibodies to cells, and without affecting the antigen-antibody combination. Thus it can allow hyposensitization of certain tissues, while preventing the release of the pharmacological mediators of anaphylaxis. The observation that cromoglycate can inhibit the release of histamine also from mast cells, supports the suggestion that cromoglycate does act as a membrane stabilizer. Non-immunological stimuli block the release of histamine-for example, the histamine-releasing substance compound 48/80,3 human plasma, dextran, and trypsin inhibitors.

Cromoglycate has no sympathomimetic, antihistamine-like, or corticosteroid-like effects. Less than 0.5% of the dose is absorbed after oral administration, and maybe up to a maximum of 5% is absorbed after inhalation of the powdered compound. When drug is given via inhalation route, little pharmacological effects are achieved in man. Animal studies relating to absorption, distribution, and excretion showed absorbed components were rapidly eliminated unchanged.

Clinical trials have shown over 2,000 patients who have had exposure to the drug varying from a single dose to a continuous dose for more than 2 years, showed no important toxic effects have been reported. Some complaints of irritation to the throat on inhaling capsule have been recorded, but this occurred with both the active preparation and with the lactose vehicle. An animal 90-day inhalation studies showed no toxic effects. The LD50 on parenteral administration to small laboratory animals was commonly between 2,000 and 4,000 mg/kg. In vitro tests showed that a concentration of at least5 mg/ml was required to produce effects on the morphology of HEp2 cells and chick embryo fibroblast cells.

Anaesthetized dogs showed intravenous injection of doses about 8mg/kg caused immediate collapse, and transient apnoea with rapid recovery. Doses as small as 10 kg elicited reflexes from the coronary and pulmonary circulations. These effects recorded were not seen in the other animal animals tested. In rabbits, the dose was given intravenously, and no teratogenic effects were seen in doses of up to 250 mg/kg. No congenital abnormalities were seen in infants born to mothers taking cromoglycate throughout their pregnancy.

The dosing schedule for Disodium Cromoglycate can be summarised as;

Adults and Children 2 yr of age and older: Oral inhalation 1 vial via nebulizer 4 times daily at regular intervals.

Mastocytosis

Adults and Children 13 yr of age and older- PO Initially 200 mg 4 times daily 30 min before meals and at bedtime. If satisfactory control of symptoms is not achieved within 2 to 3 wk, dosage may be increased (max, 40 mg/kg/day). Once a therapeutic response has been achieved, dose may be reduced to the minimum required to maintain a lower degree of symptomatology. To prevent relapses, dosage should be maintained.

Children 2 to 12 yr of age - PO Initially, 100 mg 4 times daily 30 min before meals and at bedtime. If satisfactory control of symptoms is not achieved within 2 to 3 wk, dosage may be increased (max, 40 mg/kg/day). Once a therapeutic response has been achieved, dose may be reduced to the minimum required to maintain a lower degree of symptomatology. To prevent relapses, dosage should be maintained.

Cromoglicic acid is available in multiple forms:

As a nasal spray (Rynacrom(UK), Nasalcrom, Prevalin (Netherlands)) to treat allergic rhinitis.

In a nebulizer solution for aerosol administration to treat asthma.

As an inhaler for preventive management of asthma. The maker of Intal, King Pharmaceuticals, has discontinued manufacturing the inhaled form, cromolyn sodium inhalation aerosol, due to issues involving CFC-free propellant.

Allergic Rhinitis- Adults and Children 2 yr of age and older

Intranasal Spray once into each nostril; repeat 3 to 4 times daily (every 4 to 6 h up to 6 times/day) if needed. For best results, start using up to 1 week before contact. http://www.drugs.com/ppa/cromolyn-sodium-disodium-cromoglycate.html.

Up to date clinical studies imply disodium cromoglycate may have a direct effect on inflammatory cells. This is because the drug reverses many functions such as increased membrane-receptor expression and enhanced cytotoxic capacity in white blood cells, observed in subjects with asthma undergoing allergen-inhalation challenge (reference).

A current study has shown that disodium cromoglycate at low concentrations of approximately 10(-8) mol/L, in order to produce 50% inhibition, directly inhibited the activation of in vitro of human neutrophils, eosinophils, and monocytes. Blood leucocytes activation was assessed when they were incubated at optimal concentrations of 10 -18 mol/L,with synthetic chemoattractant, formyl-methionyl-leucyl-phenylalanine,and activiation was assessed by measuring an increase in the percentages of IgG (Fc) rosettes. We also measure the enhanced capacity of these cells to kill targeted organisms- (schistosomula of Schistosoma mansoni).

It is found that disodium cromoglycate at a concentration of 10(-7) mol/L totally inhibited the formyl-methionyl-leucyl-phenylalanine-inducing activation of complement and IgG rosettes, as well as increasing schistosomular killing. Observations found indicate that disodium cromoglycate directly inhibits the secretory properties of inflammatory cells, which in turn may have important implications in modulating mechanisms contributing to the inflammatory component of asthma and allergic disease. This provides an explanation to why compounds with considerably greater mast cell stabilizing properties than disodium cromoglycate have been so disappointing when they are evaluated clinically (19).

Clinically disodium cromoglycate has been found to reduce asthma attacks and improve pulmonary function. Use of this drug may also make it possible to reduce the contaminent drugs. Best effects are obtained when disodium cromoglycate is used early into asthma treatment. When patients with moderate to severe asthma were treated with regular inhalation of disodium cromoglycate a small amount of inhaled B2 agonist there was an improvement in the patient's asthma (20).

Leukotrienes are chemicals that are released as part of a normal physiological response. They help our body deal with foreign antigens such as bacteria that we may breathe in. People with asthma may over react to certain chemicals, causing an increase in the production of leukotrienes which may cause breathing problems.

Leukotriene antagonists bind to leukotriene receptors preventing an effect from being produced. Leukotriene antagonists are available as an oral dosage form in the form of tablets. Drugs available on the market in the UK include:

montelukast (Singulair).

zafirlukast (Accolate).

These drugs may prevent asthma attacks from occurring, i.e. prevent symptoms of asthma, however they do not relieve symptoms if they occur. Hence, a quick relief inhaler is still required.

A doctor or nurse may advise a patient to take a leukotriene antagonist if the patient has previously has not responded to steroid inhalers or if the patient does not use the steroid due to side effects caused.

Leukotrienes are synthesised from arachidonic acid by a specific synthesis pathway whose key enzyme is 5-lipoxygenase. Cysteinyl leukotrienes (leukotrienes C4, D4and E4) have been shown to mimic all the pathologic changes that are characteristic of asthma (9), whereas leukotriene B4 does not appear to exert biological properties relevant to asthma. Cysteinyl leukotrienes bind to two receptor subtypes: CysLT1and CysLT2. The majority of the biological properties of cysteinyl leukotrienes relevant to asthma are mediated through CysLT1receptor stimulation. (9)

Leukotrienes cause bronchoconstriction, increased mucus production and airway inflammation, all of which are critical features of asthma. Antileukotriene drugs are developed in order to inhibit the effects caused by these lipid based mediators. Antileukotrienes are a new class of drugs, representing a new approach to asthma treatment in the past 25 yeaars. The leukotriene receptor antagonists, montelukast, zafirlukast, and pranlukast, and the 5-lipoxygenase inhibitor, zileuton, are unique in their ability to target specific components of asthmatic inflammation (reference).

The antileukotrienes have shown efficacy against exercise and allergen induced bronchoconstriction. They have an additional benefit of treating patients with symptomatic asthma varying from moderate to severe asthma involving maintenance-inhaled corticosteroids. The drugs may also be considered for primary use in patients with mild, persistent asthma, especially those who are steroid-phobic or who have compliance issues (18).

Cysteinyl leukotrienes (Cys-LTs) are mediators released in virus-induced wheezing. Corticosteroids have little or no effect on the release of these mediators. Cys-LTs are both direct bronchoconstrictors and proinflammatory substances that mediate many steps involved in the pathophysiology of chronic asthma.

Cys-LTs recruit inflammatory cells, lead to vascular leakage, and possible remodelling of airways. Studies have shown Cys-LTs are pivotal mediators in the pathophysiology of asthma. Cys-LTs are important mediators in the early and late allergic airway response produced, and in also contributing towards the bronchi obstruction after exercise. They also may cause hyperventilation of cold, dry air in asthmatics.

LT modifiers decrease the number of eosinophils and exhaled nitric oxide levels decrease, these findings show an important role of Cyst-LTs in the asthma airway inflammation. LT modifiers have an onset of action from 1 to several days; therefore LT modifiers cannot be used as emergency treatment as their effect is not rapid enough. LT modifiers possess some anti-inflammatory properties, but however cannot be substituted for the use of corticosteroids in the use of inflammatory control.

LT modifiers are substitutes for long-acting beta-agonists as complementary treatment to inhaled corticosteroids, in asthma management because they provide bronchodilation and bronchoprotection without development of tolerance. Given their efficacy, antiinflammatory activity, oral administration, and safety, LT modifiers will play an important role in the treatment of asthmatic children (8).

The drug therapy of asthma remains mainly unchanged over the past 30 years, comprising of glucocorticoids, β 2-agonists, and theophyllines. The antileukotrienes and the leukotriene antagonist represent an important new class of drugs for the treatment of asthma. . Currently the use of the 5-lipoxygenase inhibitor zileuton is restricted due to its daily four times dose regimen and to observe biochemical liver function tests regularly. The leukotriene antagonists appear to be effective against all severities of asthma, although their exact role in asthma management guidelines have yet to be established due to relatively little published database.

Inhibition of the 5-lipoxygenase pathway

Drugs such as zileuton block lipo protein oxydatenase 5-lipoxygenase, inhibiting the synthetic pathway of leukotriene metabolism, whereas drugs such as MK-886 block the 5-lipoxygenase activating protein (FLAP) and may help in treating or more complex disease atherosclerosis.

Antagonism of cysteinyl-leukotriene type 1 receptors

Drugs such as montelukast and zafirlukast inhibit the actions of cysteinyl leukotrienes at the CysLT1 receptor. They do this by targeting certain receptors e.g. receptors on bronchial smooth muscle. These modifiers improve asthma symptoms, thus reducing asthma exacerbations. They also limit the use of markers in inflammation e.g. eosinophil count in the peripheral blood and bronchoalveolar lavage fluid. This supports the fact that these drugs do have anti inflammatory properties.

A clinical study contained 72 patients which was conducted to compare the placebo effect. The placebo effect was compared to the montelukast, in which there were no significant changes found in the change of symptoms. The mean difference between the" last 7 days of each treatment period 0.05; 95% CI --0.86 to 1.14, rescue inhaled β 2-agonist use (mean difference in puffs per day 0.41; -0.29 to 0.57), or twice daily peak expiratory flow (PEF) measurements (mean difference in morning PEF 1.18 L/min; -14.29 to 17.14), and mean difference in evening peak flow (-0.50; -17.42 to 12.86)". Once response to the treatment was at 15% or greater increase in mean peak flow readings, it was found that there were four responders to montelukast and seven responders to placebo (17).

A study revealed that add-on montelukast demonstrated major improvement in asthma symptoms over a 12 month period in all the patients. Patient subgroups showed an improvement in the control of asthma, but comorbid allergic rhinitis, younger age, shorter duration of asthma, and treatment with only inhaled corticosteroids were indicators of better control. These observations may be shared with other anti-asthmatic medications and further research may be carried out (7).

There may be advantages of taking a tablet twice-daily with montelukast as an alternative to low-dose inhaled glucocorticoid for patients with mild persistent asthma. Leukotriene antagonist compliance may be reiterated by their onset of action within the first 24 hours of treatment in contrast to the more gradual effects of inhaled glucocorticoids over several weeks (16).

Leukotriene antagonists even though they have been used their effects are not thought to be as expected and promote a major response in the treatment of asthma. The add on effect does not have the desired response that is needed for suffers of chronic asthma.

Conclusion

In conclusion of the three new drug developments for the treatments of bronchial asthma introduced and used more widely in clinical practice since 2005 several comments can be made:

Firstly that Omalizumab is indicated for adults and adolescents (12 years of age and above) with moderate to severe persistent allergic asthma who have a positive skin test to a perennial aeroallergen and whose symptoms are insufficiently controlled with inhaled corticosteroids. Omalizumab has been shown to decrease the incidence of asthma exacerbations in these patients. However safety and efficacy have not been established in other allergic conditions. Clinical trials have revealed an increased incidence of malignancies in patients receiving omalizumab. However, due to the diversity of the cancers that have been observed, the relatively short period of exposure to omalizumab and the clinical features of the individual cases, a causal relationship is unlikely to be considered. This possible effect will therefore require further monitoring with increased patient exposure.

Secondly Disodium Cromoglycate clinically has been found to improve pulmonary function and reduce asthma attacks. The greatest effects are obtained when disodium cromoglycate is used early into asthma treatment. When patients with moderate to severe asthma were treated with regular inhalation of disodium cromoglycate a small amount of inhaled B2 agonist there was an improvement in the patient's asthma. Disodium cromoglycate does have an effect especially on exercise induced asthma; however studies have shown that it does not have the desired therapeutic effect on children with exercise induced asthma.

Thirdly leukotriene antagonists have shown on paper seem very promising however their effects are not as expected when put in to practice. These drugs can stop you getting asthma symptoms (attacks). They won't help with symptoms when they happen. You'll still need your quick-relief inhaler to treat symptoms when they happen. Looking back to a study carried out by Robinson et al (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)05113-8/abstract), they found that montelukast did not provide additional benefit to patients with moderate to severe asthma. Asthma is a serious condition which affects many all across the world, some have a more serious condition than others, many drugs are available however there is still requirement for many drugs as asthma is a growing condition and drugs are needed to counteract it.

Finally the treatment of bronchial asthma is 2010 is still awaiting the optimal and safe therapeutic effect.