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Asthma is an inflammatory disorder with its cases gradually increasing worldwide. If defined, asthma is basically the obstruction of the inhaled air into the airway and along with hyper-responsiveness of the tracheal bronchioles often accompanied by variation in the severity which varies along a platform of patients rendered with the disease. Asthma if diagnosed, in its earlier stages lies in a reversible situation with the use of medication, but if left untreated moves into a complicated condition were the airway becomes fixed or irreversible often referred to as COPD or Chronic Obstructive disease. It's on necessary that all asthmatic subjects may accompany COPD. The mortality due to asthma has increased in the past three to four decades, although there has been continuous research and finding newer therapies for treatment. Speaking on a global prospective, huge variations were seen among all. Patients suffering from asthma were the highest in New Zealand, Australia, North America and UK while the least in Russia, Indonesia, and Albania. Apart from the hyper responsiveness and airway obstruction a few other causative key players also modify the condition amongst which are environmental factors, allergens, irritants, air pollution, genetic buildup, association of other diseases and lifestyle differences.
Asthma is a very common disorder, accounting for about 50,000 hospital admission every year, and more pediatric hospital admission as compared to any other single illness. According to the statistical data obtained 50,000 patients including children and adults die of asthma in United States. However in the past decades, substantial progress has been made in understanding the path physiology of asthma. Asthma is no longer referred to as a simple airway obstruction or "irritable airways". Asthma is primarily an inflammatory illness with bronchial hyperactivity as a result bronchospasm. This view has led to a change in the recommendation and the medications prescribed for the prevention and treatment of asthma. For symptomatic use, simple bronchodilator therapy has shown the positive results as an anti-inflammatory drugs.
The recognition that asthmatic airway narrowing at the baseline and at the time of exacerbations is due to inflammation as studies based upon bronchial lavage and lung biopsies. Asthmatic subjects have increased number of basophils and other inflammatory cells present in the lung causing airway obstruction. Exposure to allergen partially or substantially also triggers asthmatic inflammation. Basophils and mast cells get activated by exposure to allergen. Allergen specific IgE is bound to the mast cells via Fc receptors. When allergen crosslink's to IgE molecules, basophils and mast cells are activated which in turn release a variety of mediators. Immunological stimulation of basophils also leads to the synthesis of several proinflammatory cytokines, such as Interleukin IL-4 & IL-3 all resulting in one potent effect i.e. airway inflammation.
These new cells reach the lungs the drain release mediators, adding more to the obstruction. While histamine and leukotriene released from the mast cells in acute reactions these mediators with IL-4 & IL-3 come from basophils in chronic cases. The chronic results are bronchial hyperactivity to stimuli such as allergens, pollutants, histamine,
airway edema and smooth muscle hypertrophy.
Asthmatic patients are usually free of symptoms, with only an occasional mild cases of shortness of breath. Patients also cough and wheeze and have severe asthmatic attacks after exposure to allergens, viral infections, exercise also cigarette smoke.
An attack may start suddenly with characteristics symptoms such as coughing, wheezing and shortness of breath. If left untreated, gradually worsening symptoms show up. Confusion and lethargy develops, often requiring emergency treatment is needed.
Currently available treatment for asthma:
Aerosol Delivery System:
Tropical application of drugs can be accomplished by aerosol. The crucial determination of any particulate matter depends upon the size of the particles. The two types of devices used for aerosol delivery are metered-dose inhaler and nebulizers. Both devices produce particle size of 1Âµm to 5Âµm. Metered-dose inhalers are cheap and portable while nebulizers usage doesn't require breathing coordination. An alternative to aerosolized delivery system is by powder forms. A major disadvantage of this system is that high airflow is needed to suspend the powder. Children's and elderly suffering from a severe asthma attack cannot generate such airflow, also these are irritating when inhaled.
Î²-Adrenergic Receptor agonists:
Short-acting Î²2 adrenergic agonists are usually the first preference for relieving asthma attacks. Î²2 agonists are also referred to as bronchodilators, because they activate the receptors to widen the airway path. They act on all beta-adrenergic receptors throughout the body (such asÂ albuterol, levalbuterol, metaproterenol, terbutaline) that act mainly on the one present in the lungs and the effects last only 2 to 6 hours.
Long acting bronchodilators such as Salmeterol and bitolterol but they are used for prevention rather than for attacks.
Presently Theophylline of the class methylxanthines are now used less frequently.Â TheophyllineÂ is used for both prevention and treatment of asthma. Theophylline inhibits the cyclic nucleotide phosphodiesterase enzyme (PDEs). PDE's catalyze the degradation of cAMP and cGMP to 5'-AMP and 5'-GMP respectively, which leads to the accumulation of cAMP and cGMP, hence increasing the signal transduction through these pathways. The potency and efficacy of PDE inhibitors depend upon the basal level of cyclic nucleotide production. Cyclic AMP and cyclic GMP produced in the cells is regulated by an endogenous receptor-ligand interaction leading to the activation of adenylyl cyclase and guanylyl cyclase.
Montelukast andÂ zafirlukast are highly selective, high affinity, competitive antagonists the cys-LT1 receptor. These anti-inflammatory drugs, prevents body synthesized leukotriene mediated bronchoconstriction. These drugs act either as competitive antagonist of leukotriene receptors or by inhibiting the synthesis of leukotrienes. Cysteinyl leukotrienes (cys-LTs) include LTC4, LTD4 and LTE 4. All the cyc-LT is potent constrictors of the bronchial smooth muscles.
Ipratropium an anti-cholinergic drug, blocks acetylcholine and the contraction of smooth muscle production of excess mucus in the bronchi. The efficiency increases with beta-adrenergic agonists and its combined treatment is preferred for prolonged bronchodilation. Ipratropium induced bronchodilation usually less efficacious than that produced by the adrenergic agonists.
Mast Cell Stabilizers:
Mast cell stabilizers inhibit the release of inflammatory mediators from mast cells thereby preventing the airway to less narrow. They are also anti-inflammatory in nature. Cromolyn and nedocromil are used in the treatment of mild to moderate bronchial asthma to prevent asthmatic attacks, and ineffective in the treatment of ongoing bronchoconstriction. Useful for patients who develop asthma from exercise.
Corticosteroids are the most potent form of anti-inflammatory drugs. They seize the body's inflammatory activity and are most effective in reducing asthmatic symptoms. Inhaled form is generally used to prevent attacks and improve lung functioning. Doses are modified according to the severity of attacks. Inhalation therapy is the best versions drug delivery mode to the airways and minimize the amount sent into the systemic circulation. Corticosteroids can be used in high doses to relieve a severe asthma attack and are generally prescribed for 1 to 2 weeks. Oral corticosteroids are prescribed on a long-term basis only when other treatments fail control the symptoms.
On a long term basis corticosteroids reduce the attacks by making the airways less sensitive to stimuli. Side effects produced are obesity, osteoporosis, elevated blood sugar levels.
OmalizumabÂ is an antibody, which is targeted opposite to group of other immunoglobulin antibodies called IgE.Â People having high levels of IgE in their blood and suffering from severe allergies are benefited by omalizumab. It blocks the IgE binding site on mast cells and thus prevents narrowing of the airway by inhibiting inflammatory chemicals release. Omalizumab is administered subcutaneously.
Present limitations in the treatment of asthma:
The terms: Cost, availability, refractory treatment and importantly the adverse effects:
Limitations: Adverse effects of the currently used drugs
Î² adrenergic agonists:
Inhaled Î²-adrenergic receptor agonists, at recommended doses have relatively lesser side effects, at higher doses it may lead to increased heart rate, cardiac arrhythmias and central nervous system effects.
Inhaled Glucocorticoids :
Oropharyngeal candidiasis, dysphonia can be encountered. Suppression of the hypothalamic pituitary adrenal axis.
Dose related toxicity such as mood disturbances, increased appetite, loss of glucose control in diabetes and candidiasis.
Leukotriene receptor Antagonists:
Zafirlukast and Montelukast in very rare instances, these drugs developed a systemic eosinophilia and a vasculitis with features similar to Churg-Strauss syndrome. Zileuton decreases the steady state clearance of theophylline plasma concentration and warfarin clearance.
Rapid intravenous administration of aminophylline can cause sudden death due to cardiac arrhythmia and the drug should be injected slowly. Headache, palpitation, dizziness, nausea, hypotension are frequent. Additional symptoms of toxicity are tachycardia, severe restlessness, agitation and emesis.
Mast Cell Stabilizers:
Cromolyn and nedocromil are generally well tolerated by the patients. Minor side effects, includes bronchospasm, cough and wheezing, laryngeal edema, joint swelling and pain, angioedema, headache, rash and nausea.
Limitations: Cost Availability
The total global market for asthma drugs is calculated to be about $12.92 billion in 2005 where U.S. market accounts for approximately $6.46 billion, which is approximately half of the global total. With a clear understanding of the below lying causes, better medications and improved care has been generated, as a result many people can still leave a normal life with the new therapies. But still a greater proportion of people are far from the reach of proper treatment due t their low economic strata, no medical insurance as the medications turn out to be too expensive as they are prescribed on a long term basis. Overall 43% of all people with asthma in the past year reported that, they did not have the money to afford treatment, according to the 2009 Health Costs Survey article published by Journal of Allergy and Clinical Immunology. Availability is another issues of interest as most of the poorly developed region globally are unknown of the newer clinical drugs and the branded drugs are less preferred by the distributors and retailers while the generic once prove ineffective.
Limitations: Refractory Treatment
Patients with asthma about 10% of the total cases have persistent symptoms or asthma exacerbations where high medication is required to good clinical condition. Refractory Asthma is a term that is used to classify the patients with the above mentioned clinical condition. Patients found with refractory asthma, require huge doses or combinations to maintain the disorder as their airway is narrowed and fixed and the hyperactivity and inflammation is uncontrollable to treat with any treatment regimen.
Improved Treatment: Novel therapies and novel targets
Much study has gone though in the past years to resolve the actual cause of asthma and tackling chronic or irreversible asthma. Amongst the study papers a few are being discussed below.
Impact of bronchial thermoplasty on asthma status:
Bronchial Thermoplasty (BT), a bronchoscopic procedure, reduces the amount of airway smooth muscle, which may decrease symptoms due to bronchoconstriction. 108 subjects with moderate to severe-persistent asthma requiring >200Î¼g beclomethasone The data suggest that BT treated subjects experience signiï¬cant improvements in asthma status at 12 weeks post-treatment as per the results from the IR trail.
Phosphodiesterase inhibitor has proved to be excellent drugs in the treatment. Drugs such as theophylline, which is a non specific PDE inhibitor treats airway diseases, anti inflammatory and anti fibrotic. Though newer drugs are in progress which could minimize the unwanted effects by being more specific. The result caused is due to the generation of cyclic AMP by the inhibiting its degradation.
Neurokinin receptors antagonist
Neurokinin mediated responses which induces neurogenic inï¬‚ammation is blocked by CS-003. CS-003 is a potent antagonist of triple neurokinin receptors, and prove beneficial to treat neurokinin related airway diseases.
Antagonist: H4 target receptor:
A new discovery brought a receptor H4 is found eosinophils, T-cells and mast cells, which when blocked leads to the deactivation of cell mediated chemotaxis and thereby beneficial. H1 antagonist are ineffective in these cases. JNJ 7777120 antagonist can selectivity block H4 receptors.
Preliminary evidence of bronchodilating activity of TPI 1020 (NO-budesonide)
A novel anti- inï¬‚ammatory compound synthesized by adding a nitric oxide (NO)-donating side chain to budesonide has a better bronchodilating activity than budesonide in in- vitro and in vivo models of bronchoconstriction or acute airways inï¬‚ammation.
ACZ885 is a fully humanized monoclonal antibody
A monoclonal antibody to IL-1B attenuates the late asthmatic response to antigen challenge in patients with mild asthma. ACZ885 is a fully humanized monoclonal antibody, with high affinity and speciï¬city for IL-1B.
Fudosteine, an airway secretory cell normalizer
Improving effect of fudosteine on sputum symptoms and health-related quality of life of patients with bronchial asthma. Fudosteine, an airway secretory cell normalizer, has unique inhibitory activity on hyperplasia of airway epithelial goblet cells apart from its ordinary actions of conventional expectorants.
Critical Assessment of the new and improved therapy:
Newer class of PDE 4 inhibitors such as roflumilast, piclamilast proved to be efficacious in in-vitro and in-vivo conditions.
For the assessment of newer therapy such as inhaled medications, combinations of corticosteroids and long-acting bronchodilators such as Advair, and leukotriene receptor antagonists-Singulair whether they had made a positive outcome in treatment of asthma, researchers observed a hospital with 65 children between 2006 and 2009. The results were compared with another group of 164 children between 1997 and 1999. All cases were of severe asthma.
It was found that 28% of the 65 children's group was less likely to use oral steroids against 51% of the 164 children's group. Therefore in an all, it states that about one quarter of today's formulations is sufficient to tackle attacks which is different then what it used to be 10 years earlier.
Asthma is no longer a single disease. Instead, it includes set of connected symptoms which arises due to a variety of environmental and genetic factors. These indirectly influence the rate of progression, lung function decline and response to therapy. Therefore is mandatory to view all the factors and prescribing the right therapy to the right asthma subtype. But trial and error still play a large role in making the right match. Asthma is the most commonest diseases worldwide and evidences state that both asthma and COPD are increasing. Present therapies are well tolerated but there is a need to find better treatment for patients with severe disease and emergency exacerbations with a small proportion but disproportionate medical costs.
By contrast, COPD is not still very much useful and new measures should be taken in understanding the molecular mechanism in order to find new targets and actually reduce the progression and exacerbations.