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Asthma is a respiratory disease caused by various triggering factors mainly resulting in irritation of bronchial mucosa leading to reversible bronchoconstriction and airway inflammation.(1) It is inflammation of the airways which results in narrowing of the bronchial tubes causing difficulty in breathing. These bronchial tubes may become sensitive to asthma triggering factors such as allergens and irritants . This may result in bronchial hyper activity(2) This disease is characterized by inflammatory process as well most common thickening of airway wall. There is air flow limitation which is reversible found in asthma patients. Decrease in the flow may be the result of reduced diving pressure or increased resistance.(3). Asthma caused by allergy affects large number of population of around 100 million worldwide (7).
Since 1970s significant rise in disease prevalence was seen and estimation of around 4-7% of people are affected. 20 million people in US are affected, and disease shown to be chronic in children affecting around 6 million . asthma found to be the cause of hopitalization for children and in 2002 the cost of care for treating the disease was $14 billion.(1) Based on the diagnosis rate every year and patients who were found with asthma from diagnosis incidence of asthma is known. In america 1998 about 1.7 million african americans were diagnosed for asthma and were found asthma attacks.( (CBCF Health Organisation, 2004). 5637 deaths occured due to asthma in 1995 (NHLBI),4657 deaths reported in USA 1999(NVSR Sep 2001), 5000 deaths were reported annually (NIAID). According to NHLBI 2002 estimated cost for asthma was around $6.2 billion and it is expected to increase to $14.5 billion . (4)
According to a study conducted in young adults in Italy, incidence of asthma was 15.2/10000 annualy.this incidence prediction was done by symptoms such as chest tightening, wheezing in day time, and dyspnoea during nights. (5) Even though there is a increase in prevalence of asthma , mortality rate has reduced which gives the credit to scientists for developing many therapeutics for combating the disease by knowing the conditions. Further examining the epidemiology of asthma, it shows some correlations between causes and the disease itself. Epidemiology is important for research on asthma and some times seems to be cluster of numbers .(6)
Tightening of chest,
Shortening of breath, and
wheezing are the symptoms of disease
Disease is diagnosed by knowing the history, by physical examination and some kind of pulmonary function tests. Treatment of asthma mainly involves controlling factors which triggers the disease.(1)
Two types of changes were observed in histopathological studies in patients i.e cellular changes and structural changes. Cellular changes bring out the infiltration by inflammatory cells of the air way passages and structural changes causes components of wall to become enlarged.eosinophilic inflammation feature is important in process of airway inflammation involving eosinophils , mast cells, CD4 T- Lymphocytes. outer section of airway wall contains small density and inner section has high density of eosinophils there by contributing to air flow limitation. There is an evidence of neutrophilia associated with the disease in cases on eosinophilic infiltration and also evidence of increase in neutrophils in sputum and found that this effect is mainly due to corticosteroid treatment with reduction in eosinophils and inhibiting neutrophil death. No contribution of neutrophils in pathological process which are present in air ways, but arte there only for representing severity. Mucus pluggings were formed causing closure of airways by an increased surface tension . this increased mucus secretion is due to hypertrophy as wel as hyper plasia of globet cells. Enlargement of reticular basement membranes is due to collagen deposits of collagen I,III,V .(3)
Asthma is caused mainly due to triggering factors . whenever such antigens such as pollen or house dust mites attack , there is production of IgE antibodies(immunoglobulin E) which settle in circulating blood or bind to mast cells or basophils.(8) Asthmatic patients have both T-helper 1 cytokines , interleukin-1beta, interferon (INF-GAMMA), TNF-ALPHA, and T-helper 2 cytokines(th2) IL-4,IL-5,IL-10,IL-13. The main reason for inflammatory action is the imbalance between Th1 and Th2 cytokine responses.(10). On initial reaction , antigen and antibody complexes bind to mast cells or basophils and results in release of mediators by degranulation process. Mediators such as histamines , protease enzymes, TNF ALPHA, are released from the granules immediately on reaction and phospholipids such as PGS, LTS, PAF released from cell membranes within minutes and also gene activation is seen. These mediators are responsible for inflammation and constriction of bronchial smooth muscles and producess excess mucus secretion. Air flow obstruction is observed and inflammation spreads from cell to cell leading to formation of more inflammatory cells . air remodelling increases the risk of disease. (9) Leukotriene and cytokine mediators released from mast cells activates eosinophils , basophils and macrophages which lead to excess production of mediators and disease progression.some other factors released as mediators include adenosine (acting as local hormone) which helps in maintaining bronchial tone, various neuropeptides, and platelet activation factor. Bronchoconstriction and mucus secretion are enhanced by increased levels of cGMP levels on release of acetylcholine. Neuronal mediators such as non-adrenergic and non-cholinergics play a role in affecting airflow.(8)
2. PAST TREATMENTS:
Asthma is used to describe breathlessness in the past by ancient Greece. Previously Chinese healers considered that wheezy breathing was a sign of imbalance in life force, and that they restored by acupuncture, massage, diet, and exercise . Hindu philosophers restored control on breathing by yoga . Sir William Osler was the one who suggested that inflammation plays a major role in asthma. Inflammation caused is associated with production of IgE antibody and Th2 responses.(7) During 1950s bronchodilators were used in treatment and were improved for treatment and control of asthma. Later corticosteroids occupied the place as main stay in treating asthma due to its effective anti-inflammatory action. as per statistics, cases of asthma and annual rate of hospitalization showed 30% over past 20 years. Presence of inflammatory cells such as eosinophils , lymphocytes, and mast cells in bronchial tubes present them as important targets for allergic inflammation. Main goals of treatment are, controlling inflammation for minimizing the reactivity of airways in short term and prevention of permanent thickening of bronchial walls.(2)
Belladonna alkaloids started its use for asthma treatment in 1905 and are still used today. It was available as asthma cigarettes and addition of stramonium was useful in ttreatment of asthma paroxysm. Mechanism of action was not known but they were useful in bronchoconstriction inhibition. In 1914, first line choice drug were the anticholinergics which were given in form of injection or inhalation. In 1980s ipratropium bromide was developed and it is not approved by U.S.FDA. Bronchodilators such as methyl xanthines were used as effective treatment but had much side effects. In 1970s beta2 agonists were developed such as albuterol. They showed rapid onset and excellent bronchodilator action.(18). These medications showed limited use in traeating asthma as the mechanism of disease was not known. So, newer formulations have been developed covering the limitations of past treatments.
3. CURRENT TREATMENT:
Even though there are many therapies available worldwide , mortality and morbidity rates are still increasing rapidly.(citation).there is a need for developing strategies for controlling the disease by conducting further research. Current treatments available for treating asthma include BETA2 agonists , glucocorticoids , theophylline , cromones , and anti cholinergic agents. Choice of treatment is based on the effect whether it is acute or severe . currently aerosol therapy is in advance as disease is affecting respiratory system,there will be localized effect on using inhalant drugs devices.by aerosol therapy systemic side effects derived from other oral preparations are reduced due to inhalation of very smaal doses to a particular site of action. Inhaled glucocorticoids are extensively used medications for asthma .(11) They produce less side effects as they are least absorbed in systemic circulation and are suitable for prolonged administration(8). They act by inhibition of cells that are responsible for inflammation.they help in preventing asthma exacerbations. They have a targetting action on macrophages , T-lymphocytes , dendritic cells and eosinophils. Glucocorticoids inhibit the gene expression by blocking transcription factors in epithelial cells of airways. Evidences are increasing in improved lung function when compared to treatment with bronchodilators and can be suitable for patients with chronic asthma. Glucocorticoids are only approved therapy which showed decrease in airway inflammation. The advancement in treating the disease have led glucocorticoids as first line therapy in both chidren and in adults asthma.BETA 2 agonists exhibits their action on BETA 2 receptors present on smmoth muscles cells of airways. It produces a reversible effects of that broncho constrictor substances such as leukotriene D4, acetylcholine , PG, and histamines. They have stabilizing action on mast cells. Cholinergic transmission occuring in human airways can also be inhibited by BETA 2 agonista there by reducing broncho constriction.BETA 2 agonists lack anti inflammatory action and therefore it is limited for its use as monotherapy. Its is mostly prescribed alomg with inhaled glucocorticoids .patients compliance can be improved on using combination of both. Fixed dose combination inhalers will be likely more popular in near future. Theophylline has been used for past 50 years for treatmentof asthma. Some recent evidences shows that it may represent anti inflammatory or immuno modulatory effects even at low doses . it has effect on lymphocyte load in airways. It is shown to be beneficial for nocturnal asthma. It is recommended as third choice of treatment after gluco corticoids. Cromolyn sodium and nedocromyl sodium are the drugs belong to cromones class . they have proven evidence of thier efficacy in combacting the disease by blocking bronchospasm effectively. They have no side effect profile and considered safe for use in asthma control. Major limitation of this drug is . this drug is not cost effective. It is expensive than other inhaled medications. Patient compliance also very much limited because of its dosing schedule(should be taken 4 times daily). Inhaled Anti cholinergic bronchodilators are currently available to minimize systemic muscarinic effects. Ipratropium bromide and oxitropium bromide have shown no side effects because of very less systemic absorption.(11)
3.1 LIMITATIONS OF CURRENTLY AVAILABLE TREATMENTS:
None of the treatment available now has a cure for the disease. The most effective treatments are also administered by inhalation making it inconvenient for few patients. Compliance of the patients is poor due to complex dosage regimens. Main limitation is the poor responsiveness of the currently available therapies in patients with severe asthma may be as a result of steroid resistance. Glucocorticoids withdrawal after long term treatment in asthmatic patients results in recurrence of symptoms. Even though cortico steroids are considered as first line treatment drug, they too have some side effects profile. They show very less effect on LTs release. (11) Use of this current medications is limted because they are short lived and mostly exhibit their effects through membrane bound receptors. (12)
4. NOVEL THARAPEUTICS:
The evidence for differing and increasing prevalence is not clear . understanding the pathophysiology of the disease led to the development of many new drugs and some drugs are still under development.(13) When these drugs enter the market with proven efficacy and reliable data ,there are chances of reducing the prevalence of asthma condition worldwide. The expectation of this treatments are more due to development of drugs by understanding the novel targets of treatment and underlying pathophysiology.
Corticosteroids are considered as first line therapy class for their long term treatment. But they have shown side effects such as bone metabolism, suprresion of HPA axis and few metabolic side effects.
Development of dissociated corticosteroids can keep the place of regular corticosteroids where, there may be chances of reducing side effects.theophylline , a PDE inhibitor which has been used from past 50 years in treatment of asthma are less expensive but because of narrow therapeutic window they are considered as third line treatment . blocking antibodies to cytokine receptors and inhibiting pro-inflammatory cytokines could be used as novel alternative treatment.
A novel therapy targeting IgE has been developed for treatment of asthma which proved to be safe .Omalizumab a recombinant anti IgE drug shown to reduce symptoms of asthma , exacerbations and improves lung functions ,quality of life , and has steroid sparing effect.even though cost of the treatment is more, cost of care for using emergency departments should be considered, as it reaches 43%.(13) Omalizumab is a novel conventional treatment strategy for asthma condition.it is a recombinant monoclonal anti IgE antibody which has proven efficacy for allergic diseases and exhibits anti-inflammatory activity. omalizumab exerts its action by binding to IgE and results in inhibiton of released mediators and thus weakening early as well late phase responses to asthma causing allergans. it has shown reduction in IL 13 and also reduction in eosinophilic count by which it can reduce inflammation.this study showed apoptosis of eosinophils and also reduction in GM-CSF required for growth. further studies should be conducted on omalizumab of proven efficacy for further focus on anti-inflammatory action for reducing release of mediators .(14) Omalizumab(xolair) is approved by FDA recently and is available now only for small number of patients.Many researchers are working for developments of new approches for finding the cure for asthma.(15)
Due to limitations of conventional anti asthmatic drugs and various hazardious effects with corticotherapy, it led the patients prefer complememtary and alternative medicines .(10) Alternative treatments for asthmatics are available which can be prescribed as an adjuvant treatment to the normal medications. These treatments will be much beneficial in case of resistance of standard therapy drugs to asthma patients. Further research on complementary treatment can bring light in future care for asthmatics with available cure and no side effects.(16) Herbal remedies have been used for past hundreds of years for the treatment of asthma . only few drug compounds have undergone clinical evaluation on their anti-asthmatic effects. BETA sitosterol , an extract from the seeds of Moringa oleifera (moringacaece) plant showed tremendous decrease in asthma symptoms and also improved peak expiratory flow rate . research results of BETA sitosterol in ovalbumin induced inflammation in guinea pigs showed reduction in synthesis of cytokines and histamines and its efficacy was evaluated against histamines , acetylcholine induced bronchospasm, which confirmed its bronchodilator action. Some invitro studies conducted showed increase in Th1 cells and decrease in Th2 cytokine functioning . reports suggests that this drug could possibly control inflammatory process and asthma exacerbations , there by decreasing the level of TNF-ALPHA, IL4,IL5,in sreum. Thus BETA-sitostrol with proven evidence may be of great benefit in future in controlling asthma.(7)
Acupuncture is one of the novel therapeutics which should be concentrated more for the further research in treatment of asthma. Preclinical studies in rats have shown good results in reducing eosinophili infiltration into tissues and also in bronchoalveolar lavages(BAL). Its effects on mediators of asthma are on study now. Acupuncture is followed in western countries and WHO considered this technique as a adjunct approval for management of asthma. Previous studies showed a marked reduction in inflammation and eosinop[hilic infiltration in BAL. Recent studies shown significant increase in Th1 cytokines release along with IL1 and IFN-ALPHA, and decrease in Th2,IL4,IL10,NO, and LT D4 with out any side effect profile . This effect regulated the balance between Th1 and Th2 cytokines . it has got both anti inflammatory as well as immunomodulatory action paying a way in increased development of complementary treatments for asthma cure . Further research is required to study the mechanism. (10).
A study conducted on a bptoanical mixture AKL 1 to investigate its effectives in treatment for patients with asthma. Botanical mixture showed no significant effects on lung function when compared to placebo but there was improvement in patients outcomes and asthma relative health status scores . AKL 1 mainly focus on affecting manifestations of the disease irrespective of bronchospastic phenomena and lead to improving symptoms. Tolerability proves to be best.research is mostly consired for its use as an add-on therapy to investigate effects on exacerbation , health status , and control of symptoms.(17)
4.1 NOVEL THERAPEUTIC TARGETS:
By knowing about the disease cellular and molecular mechanism , novel targets can be identified for development of newer drugs. Improving the current available therapies , understanding about the targets, and concentrating on new compounds based on serendipity , there is a way for development of new treatment models.
Some studies suggest that rise in cAMP levels and decrease in calcium ion concentration can lead to bronchodilation. Targeting this site can lead to development of newer drugs.
Stimulation of adenyl cyclase involves action of Gs which may irreversivly stimulated by cholera toxin. Inhibition of STAT -6 gene leads to removal of IL-4 gene which is responsible for production of IgE antibodies by B-lymphocytes.IL4 and IL13 are closely related . Thus endogenous STAT inhibitor a supressor of cytokine signalling (SOCS) acts as a new target for development of drugs.
PDE 4 D has some important cells such as eosinophils and T-lymphocytes which may be a specific target for disease.(11)