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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. 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 frequently associated with atopy, which is the genetic susceptibility to produce IgE to common environmental allergens. 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. In children wheezing also occurs during a viral infection, allergies or a family history of allergies is the strongest associated factor with recurrent asthma throughout childhood. 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 like, animal products, wood dusts plastic resins and biological enzymes can also cause asthma (4).
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.
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. 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 (6). 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 , leukotriene antagonists, immunoglobulin E antagonists (omalizumab) and sodium cromoglycate. First of all the 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 eicosanoid lipid mediators. Leukotrienes are thought to have a role in both autocrine signalling and paracrine signalling so as to regulate the body's response. Leukotrienes are produced in the body from arachidonic acid by the enzyme 5-lipoxygenase. These agents are not stored inside a cell but are always made "de novo", on demand and then they exert their physiological effects.
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" 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 used to treat those diseases because of their convenience (and perceived safety), leukotriene receptor antagonists have largely replaced it as the non-corticosteroid treatment of choice
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.
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
Omalizumab is a humanised antibody drug approved for patients with moderate-to-severe or severe allergic asthma, which is caused by hypersensitivity reactions to certain environmental substances. Omalizumab's cost is high ($10,000 to $30,000 per year), as compared to other drugs used for asthma, and hence omalizumab is mainly prescribed for patients with severe, persistent asthma, which cannot be controlled even with high doses of corticosteroids. Like other protein and antibody drugs, omalizumab may potentially cause anaphylaxis (a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000.
Cromoglicic acid is described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium. This drug prevents the release of inflammatory chemicals such as histamine from mast cells. (Cromoglicic acid requires administration four times daily, and does not provide additive benefit in combination with inhaled corticosteroids).
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.
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.
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.
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). IgE is commonly involved with allergies when present in high amounts in the body.
Omalizumab (Xolair, Novartis Pharmaceuticals UK) is a recombinant humanised monoclonal antibody that inhibits the binding of IgE to high affinity receptors (FcÎµRI) on the surface of mast cells and basophils. It prevents the release of pro-inflammatory mediators and reduces allergen-induced airway reactions. Omalizumab is licensed as add-on therapy to improve asthma control in adult and adolescent patients (12 years and older) with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and who have reduced lung function (forced expiratory volume in 1 second, FEV1 < 80% ) as well as frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta-2 agonist. The licensed indication states that omalizumab treatment should only be considered for patients with convincing IgE mediated asthma. 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. Treatment with omalizumab should be initiated by specialists who are experienced in the diagnosis and treatment of severe asthma. If in the longer-term continuing treatment responsibility is to be transferred to primary care, comprehensive shared care arrangements need to be implemented. Treatment dose depends on patient weight and baseline IgE level. Doses range from 75mg every four weeks to 375mg every two weeks, therefore annual costs per patient will be between £3,074 and £18,444. (Cost per annum for an average 70kg patient with serum IgE level of 200-300IU/ml would be £12,300). The manufacturer estimates a prevalence of 10-11 patients per 100,000 population. http://www.nyrdtc.nhs.uk/docs/eva/Omalizumab.pdf
Omalizumab is not licensed for use in children less than 12 years of age although patients from 6 years and over were included in some of the initial trial populations. There are on-going efficacy and safety studies involving children of this age group and this may be an area for future licence 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
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. Omalizumab is recommended, within its licensed indication, as an option for the treatment of severe persistent allergic (IgE mediated) asthma as add-on therapy to optimised standard therapy, only in adults and adolescents (12 years and older) who have been identified as having severe unstable disease.
Figure 2: Diagram representing Omalizumab binding to IgE, preventing mast cell activation. (source: http://www.clinicalpharmacy.org.uk/May/Omalizumab.pdf)
Omalizumab add-on therapy should only be initiated if the patient fulfils the following criteria of severe unstable allergic asthma.
â€¢ Confirmation of IgE mediated allergy to a perennial allergen by clinical history and allergy skin testing.
â€¢ Either two or more severe exacerbations of asthma requiring 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
The most common side effects of omalizumab treatment are bruising, erythema and pain at the site of injection. Rare side effects include increased risk of parasitic infections, anaphylaxis, usually within 2 hours of the first injection and possible drug- induced malignancies. The prescribing information has been revised based on post marketing surveillance data and indicates that allergic reactions, including anaphylaxis and anaphylactic shock, may occur beyond 2 hours and sometimes beyond 24 hours of first injection. Patients should be informed that such reactions are possible and prompt medical attention should be sought if allergic reactions occur.
The availability of omalizumab for children aged 6 to 11 years will provide an additional treatment option for patients who have exhausted other forms of therapy. Omalizumab was effective in reducing asthma exacerbations as an adjunctive therapy to inhaled steroids, and during steroid tapering phases of clinical trials. Omalizumab was generally well tolerated, although there were more injection site reactions with omalizumab. Patient and physician assessments of the drug were positive. Further assessment in paediatric populations is necessary, as is direct double-dummy comparison with ICS (15).
The cost of omalizumab will vary dramatically depending on the dosing schedule required. One 150mg vial costs £256 (excluding VAT), so the cost of therapy for a patient receiving 75mg every 4 weeks would be £3,328 per year, and a schedule of 375mg every 2 weeks would cost £19,968 per year. Nursing administration times also need to be taken into account (vials take at least 20 minutes to reconstitute), plus the required monitoring and assessments.
Pharmacists and other staff involved in the administration of omalizumb should be aware of the risk of allergic reactions to the drug, including anaphylaxis and anaphylactic shock. Such reactions are uncommon (an incidence of less than 1 in 1,000), and usually occur within 2 hours of administration, although they can occur more than 24 hours after injection.
Treatment for anaphylactic reactions (e.g. an adrenaline auto-injector [EpiPen]) should always be available for immediate use following administration should the need arise. Patients should be educated about the signs of such reactions, and advised to seek prompt medical attention if they 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 the drug, first described and recently reviewed by Cox,",2 has been studied in a variety of laboratory preparations and in patients with airways disease.
There are differences of detail between species, but the principal effect of cromoglycate is to inhibit the degranulation of sensitized mast cells which otherwise occurs after a challenge by antigen. The interaction of antigen with cell-bound antibody results in the release of pharmacologically active substances including histamine, 5-hydroxytryptamine, and slow-reacting substance concerned in anaphylaxis.
The inhibition by cromoglycate is not specific to mast cells sensitized by heat-labile reagin (IgE) but is effective when the antibody is heat-stable IgGa and in other systems. Cromoglycate inhibits the release of the spasmogens (apparently by stabilizing the mast cell membrane) only if it is present when the antigen-antibody comnbination takes place and not after the reaction has started. It does this without affecting the fixation of the reaginic antibodies to the cells or the combination of antigen with antibody. Thus it can allow hyposensitization of certain tissues while preventing the release of the pharmacological mediators of anaphylaxis.The suggestion that cromoglycate acts as a membrane stabilizer is supported by the observation that it can also inhibit histamine release from mast cells by non-immunological stimuli-for example, the histamine-releasing substance compound 48/80,3 human plasma, dextran, and trypsin inhibitors.4 Cromoglycate has no sympathomimetic, antihistamine-like, or corticosteroid-like effects. A very small proportion (less than 0 5%) of a dose of the drug is absorbed after oral administration and possibly up to 5% after inhalation of the powdered compound. When given by inhalation it has few general pharmacological effects-none that can be detected in man. The absorption, distribution, and excretion have been studied mainly in laboratory animals. The absorbed component is rapidly eliminated unchanged in the urine and bile and no accumulation can be detected.
Published clinical trials have now described over 2,000 patients who have had exposure to the drug varying from a single dose to continuous use for more than two years, and no important toxic effects have been reported. Some patients have complained of irritation of the throat on inhaling the capsule, but this has occurred both with the active preparation and with the lactose vehicle. In animals no toxic effects were found in 90-day inhalation studies. 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 least
5 mg/ml was required to produce effects on the morphology of HEp2 cells and chick embryo fibroblast cells. In anaesthetized dogs, however, intravenous injection of doses of about 8 mg/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 did not occur in other animals tested. No teratogenic effects were seen in rabbits in which the compound was given intravenously daily throughout pregnancy in doses up to 250 mg/kg.1 There havebeen no reports of congenital abnormality in infants born to mothers taking cromoglycate throughout 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.
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 (Intal) 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. As stocks are depleted, this inhaler preparation will no longer be available to patients.
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
Recent clinical studies indicate that disodium cromoglycate may have a direct effect on inflammatory cells because the drug reversed various changes in leukocyte function, such as increased membrane-receptor expression and enhanced cytotoxic capacity observed in peripheral white blood cells from subjects with asthma undergoing allergen-inhalation challenge. In the present study, we have demonstrated that disodium cromoglycate, at low concentrations (a concentration of drug required to produce 50% inhibition, approximately 10(-8) mol/L) and in a time-dependent fashion, directly inhibited the activation in vitro of human neutrophils, eosinophils, and monocytes. Peripheral blood leukocytes were incubated with the synthetic chemoattractant, formyl-methionyl-leucyl-phenylalanine (at an optimal concentration of 10(-8) mol/L), and activation was assessed by measuring increases in the percentages of complement and IgG (Fc) rosettes as well as the enhanced capacity of these cells to kill target organisms (schistosomula of Schistosoma mansoni).
Disodium cromoglycate at a concentration of 10(-7) mol/L totally inhibited both the formyl-methionyl-leucyl-phenylalanine-induced enhancement of complement and IgG rosettes, as well as increased schistosomular killing. These observations indicate that disodium cromoglycate directly inhibits the secretory properties of inflammatory cells and that in turn might have important implications in modulating mechanisms contributing to the inflammatory component of asthma and allergic disease. It may also help to explain 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 everyone actually makes in normal physiological responses. They help your body deal with infections and things like bacteria that you breathe in. If you have asthma, your body overreacts when you breathe in certain things. So you make extra leukotrienes. They are one of the chemicals can cause your breathing problems.
Leukotriene antagonists bind to leukotriene receptors preventing them from producing an effect. They can be taken as tablets. We've listed the two leukotriene antagonists (and their brand names) available in the UK:
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.
Your doctor or nurse may advise you to take a leukotriene antagonist if you've tried using a steroid inhaler but it didn't work. Or you may not want to use a steroid inhaler because of its side effects
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, whereas leukotriene B4does not appear to exert biological properties relevant to asthma. Cysteinyl leukotrienes bind to two receptor subtypes: CysLT1and CysLT2. Most of the biological properties of cysteinyl leukotrienes relevant to asthma are mediated through CysLT1receptor stimulation. (9)
Leukotrienes have been shown to cause bronchoconstriction, increased mucus production, and airway inflammation, three critical features in asthma. Antileukotriene drugs were developed to inhibit the effects of these lipid mediators. This class of drugs represents the first new approach to asthma therapy in 25 years. 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. Although the role of these drugs continues to evolve, the antileukotrienes have demonstrated efficacy against exercise and allergen-induced bronchoconstriction and additive benefit for use in patients with symptomatic, moderate asthma on maintenance-inhaled corticosteroids. Further, they may 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 asthma and virus-induced wheezing. Corticosteroids appear to have little or no effect on this release in vivo. Cys-LTs are both direct bronchoconstrictors and proinflammatory substances that mediate several steps in the pathophysiology of chronic asthma, including inflammatory cell recruitment, vascular leakage, and possibly airway remodeling. Blocking studies show that Cys-LTs are pivotal mediators in the pathophysiology of asthma. Cys-LTs are key components in the early and late allergic airway response and also contribute to bronchial obstruction after exercise and hyperventilation of cold, dry air in asthmatics. LT modifiers reduce airway eosinophil numbers and exhaled nitric oxide levels. Together these findings support an important role for the Cys-LTs in the asthma airway inflammation. Cys-LT receptor antagonists (Cys-LTRA) are generally well-tolerated. Phase III randomized, controlled clinical trials (RCT) show that LT modifiers are moderately effective, apparently with a particular between-patient variability in their clinical response. The clinical effects of LT modifiers are additive to those of beta-agonists and corticosteroids. The onset of action of LT modifiers is within 1 to several days, and not rapid enough to make them useful as rescue treatment. Although LT modifiers possess some antiinflammatory activity, they cannot substitute for corticosteroids for inflammation control. LT modifiers are alternatives to long-acting beta-agonists as complementary treatment to inhaled corticosteroids in pediatric asthma management because they provide bronchodilation and bronchoprotection without development of tolerance, and complement the antiinflammatory activity unchecked by steroids. In addition, the Cys-LTRA montelukast has been shown to ameliorate asthmatic symptoms and provide bronchoprotection in asthmatic preschool children from 2 years of age, which is of particular importance in this difficult-to-manage group of asthmatics. 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 has remained essentially unchanged over the past 3 decades, comprising use of glucocorticoids,Î² 2-agonists, and theophyllines. The antileukotrienes and particularly the leukotriene antagonists represent an important new class of drug therapy for asthma. At present, the use of the 5-lipoxygenase inhibitor zileuton is somewhat limited due to its four-times-daily dosing regimen and the need to monitor biochemical liver function tests. The advantages of the available leukotriene antagonists are the use of once-daily (montelukast) or twice-daily (zafirlukast) dosing in terms of improved compliance, as well as there being no need to routinely monitor liver function. The leukotriene antagonists seem to be effective over a wide range of asthma disease severity, although their precise role in asthma management guidelines has yet to be established due to the relatively small published database on long-term clinical efficacy.
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
Agents such as montelukast and zafirlukast block the actions of cysteinyl leukotrienes at the CysLT1 receptor on target cells such as bronchial smooth muscle. These modifiers have been shown to improve asthma symptoms, reduce asthma exacerbations and limit markers of inflammation such as eosinophil counts in the peripheral blood and bronchoalveolar lavage fluid. This demonstrates that they have anti-inflammatory properties
In one study 72 patients had diary data for analysis. Compared with placebo, addition of montelukast did not result in any significant change in symptom scores (mean difference between the last 7 days of each treatment period 0.05; 95% CI --0.86 to 1.14), rescue inhaled beta(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). When treatment response was defined as a 15% or greater increase in mean peak flow readings, there were four responders to montelukast and seven responders to placebo. (17)
Initial therapy with leukotriene receptor antagonist is not likely to be as effective as initial therapy with ICS. Biomarkers of airway inflammation such as sputum cell counts and exhaled nitric oxide are probably not necessary to treat patients with mild intermittent asthma. (6)
Add-on montelukast demonstrated significant improvement in asthma symptoms over 12 months in all patients in the study. Asthma control was improved in all patient subgroups, but comorbid allergic rhinitis, younger age, shorter duration of asthma, and treatment with only ICS and not ICS+LABA were indicators of better control with add-on montelukast. These observations may likely be shared with other antiasthmatic medications and should be further explored (7)
There are perhaps compliance arguments in favor of using a once- or twice-daily tablet with montelukast as an alternative option to low-dose inhaled glucocorticoid for patients with mild persistent asthma, in keeping with the current US guidelines.4 The compliance factor with leukotriene antagonists may be reinforced by their peak onset of action within the first 24 h 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.
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 asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately 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 shown an increased incidence of malignancies in patients receiving omalizumab. However, due to the diversity of the cancers observed, the relatively short duration of exposure to omalizumab and the clinical features of the individual cases, a causal relationship is considered to be unlikely. This possible effect will require further monitoring with increased patient exposure.
Secondly Disodium Cromoglycate clinically has been found to reduce asthma attacks and improve pulmonary function 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. 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.