New Asthma Cure

Asthma Free Forever Ebook

Jerry Ericson is a researcher and alternative medical practitioner. Jerry created this asthma treatment book basing on over 20 years of his personal experience in helping asthma sufferers relieve their symptoms within minutes, and get rid of asthma permanently without medications. This downloadable eBook format of the program is all about suggesting you right kind of lifestyle and strategies towards keeping the symptoms of asthma at bay and initializing the complete treatment to get you back to the normal life. Devised by inputting his self tested asthma recovery solutions, Mr. Ericson has got it right as there are many positive feedbacks are coming across all the corners enough to advocate the use and relief by this digital product. Conventional medicine offers no real solution to the seventeen million Americans suffering from this disease. But in this remarkable book, Jerry Ericson, shares his natural alternative that can help asthma sufferers worldwide break the bonds of asthma forever in only minutes a day! More here...

Asthma Free Forever Overview

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I usually find books written on this category hard to understand and full of jargon. But the author was capable of presenting advanced techniques in an extremely easy to understand language.

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Asthma And Chronic Obstructive Pulmonary Disease

Studies have shown increased oxidative stress in patients with chronic airflow limitation (Ochs-Balcom et al 2005) and accumulating evidence suggests that dietary antioxidant vitamins are positively associated with lung function (Schunemann et al 2001), with serum beta-carotene levels being associated with improved FEV- (Grievink et al 2000). Thus it has been suggested that antioxidant protection is important for protecting the lungs against high oxygen levels and that oxidative stress may contribute to respiratory pathology such as asthma (Rahman et al 2006, Wood et al 2003). Studies on the correlation between serum beta-carotene levels and asthma, however, have produced mixed results. One small study of 1 5 asthmatic subjects and 16 healthy controls found that despite similar dietary intake, whole blood levels of total carotenoids, including beta-carotene, lycopene, lutein, beta-cryptoxanthin and alpha-carotene, were significantly lower in the asthmatics with no differences in...

Asthma and Allergy Foundation of America A

Patient organization dedicated to improving the quality of life for children with asthma and allergies through education, advocacy, and research. The Asthma and Allergy Foundation of America (AAFA) a not-for-profit organization founded in 1953, provides practical information, community-based services, support, and referrals through a national network of chapters and educational support groups. AAFA also sponsors research toward better treatments and a cure for asthma and allergic diseases. (For contact information, see Appendix I.)

Stable Asthma in Adults

A very large number of studies have compared the bronchodilator potential of various anticholinergic agents with that of adrenergic agents in patients with asthma. (There are at present no definitive publications of the effects of tiotropium in asthma, nor is this agent approved in the United States for the treatment of asthma.) While many of these studies are flawed by the fact that they used recommended doses rather than optimal doses, they provide useful information about the comparative actions of these bronchodilators (25). Figure 4, which is typical of most such studies, illustrates many of these points. Ipratropium bromide is slow to reach peak effect, typically 30 to 60 minutes, compared with about 15 minutes for short-acting adrenergic agents. Their peak effect is almost invariably less than that of agents such as albuterol but their duration of action is slightly longer. (Tiotropium bromide is even slower to reach peak effect than ipratropium and is thus not appropriate for...

Stable Asthma in Children

Evidence to support the use of an anticholinergic agent in stable childhood asthma is unclear. Two consensus reports reviewed the published evidence and concluded that although ipratropium was safe for the pediatric population, its benefit compared with an adrenergic agent alone was slight at best (30,31). However, there are reports that the addition of an anticholinergic augmented the bronchodilation due to albuterol alone in children aged 10 to 18 years (32). There are also scattered reports of ipratropium use in other pediatric conditions such as cystic fibrosis, viral bronchiolitis, exercise-induced bronchospasm, and bronchopulmonary dysplasia, but these do not provide strong and consistent evidence for the benefit of ipratropium over alternative bronchodilators.

Acute Severe Asthma in Pediatric Patients

For acute severe asthma in children, two well-conducted trials in the 1980s showed that the addition ofipratropium accelerated the rate ofimprovement in airflow over albuterol alone (36,37). Subsequent studies (38-43) have yielded conflicting results regarding the efficacy of combined therapy, although some of these studies lacked statistical power. A systematic review (44) of 10 studies concluded that combination therapy with multiple doses of ipratropium was safe, improved lung function, and reduced hospitalization rates, especially in children with severe asthma. As in adult status asthmati-cus, therefore, an anticholinergic alone is not recommended in status but the combination of ipratropium with an adrenergic agent is probably more effective than albuterol monotherapy, particularly in severe exacerbations.

Combinations with Other Bronchodilators

Combinations of bronchodilators often result in greater bronchodilation than do single agents. Possibly this is partly due to the fact that most clinical studies are performed with recommended rather than optimal doses of the agents. An additional consideration may be that anticholinergic, adrenergic, and methylxanthine agents work by different mechanisms, affect different-sized airways, and have different pharmacodynamic and pharma-cokinetic properties, their combination is thus rational. No unfavorable interactions between these three classes of agents have been reported, so the greater bronchodilation achieved by their combination is achieved without increasing the risk of side effects. In practice, it is common to use two or even all of these agents concurrently in airways obstruction, particularly when severe. Fixed combinations in a single-delivery device are more convenient for patient's use and thus likely to lead to greater compliance. Single MDIs combining different classes...

Reduction in Airways Inflammation

Corticosteroids not only have a wide range of anti-inflammatory effects in vitro, but also cause a reduction in airways inflammation when inhaled by asthmatic patients (1,2). This evidence comes primarily from bronchial biopsy studies demonstrating that regular treatment with ICS such as beclo-methasone dipropionate (BDP), budesonide, and fluticasone propionate (FP) cause a marked reduction in the number of mast cells, T lymphocytes, and eosinophils in the epithelium and submucosa (3-8). There is also a reduction in inflammatory cell activation, as reflected by decreased concentrations of cell-derived mediators in bronchial lavage fluid (9-11). At the cellular level, ICS suppress both acute and chronic inflammation, irrespective of the underlying cause, by inhibiting many steps in the inflammatory process (Fig. 1). The disrupted epithelium is restored and the ciliated cell goblet cell ratio is normalized with long-term treatment (3). There is also some evidence of a reduction in the...

Airways Inflammation

The dose-response relationship for ICS in terms of modifying underlying airways inflammation has also been determined. While most studies have attempted to investigate this issue through measurement of surrogate markers, including inflammatory cells in sputum or exhaled gases, these are indirect indices of uncertain relevance (51,52). A more informative method has been to investigate the nature and magnitude of airways inflammation through the detailed assessment of bronchial biopsies. Utilizing this approach, Wallin et al. (53) found no significant difference in markers of airway inflammation between a dose of 400 mg and 1000 mg day of FP. This finding was derived from the measurement of submucosal mast cell and eosinophil numbers in bronchial mucosal biopsies after 12 weeks of

Incorporation with an Asthma Self Management Plan System of Care

The asthma self-management plan system of care represents an approach whereby patients are given the ability to recognize worsening asthma, and are provided with written guidelines for the appropriate medical response (131). Asthma self-management plans have been shown to be effective in the treatment of asthma, leading to significant reductions in morbidity and improved outcomes (132-134). ICS therapy forms the basis of long-term management within this system, with patients taking twice-daily ICS as regular therapy (in addition to an inhaled short-acting p-agonist as required) and being instructed to increase the dose (or initiate therapy) for worsening asthma (Table 1). There is conflicting evidence as to whether the instruction to increase the dose of ICS during an exacerbation contributes to the improvement in asthma control noted with this system of care, and whether any such improvement is due to the pharmacological effect of the higher dose, or through changes in patient...

Emergency Treatment of Severe Asthma

A clinical situation that has recently been investigated is the use of high doses of ICS in the emergency treatment of severe attacks of asthma (48-50). The rationale for such an approach includes the delivery of steroid directly to the airways, lower systemic side effects, and a greater efficacy in reducing BHR compared with oral steroids. A systematic review of the seven trials that have investigated this indication identified that inhaled steroids may reduce hospital admission rates by about half in patients with acute severe asthma (50). In contrast, ICS did not achieve clinically important changes in pulmonary function or symptom scores. Furthermore, it was unclear if there was a benefit of ICS when used in addition to systemic corticosteroids. As a result, further research is required to determine the effects of ICS in acute severe asthma, in particular comparing the use of ICS with oral steroids, the dose-response relationship, and whether ICS have efficacy when used in...

Leukotriene Modifiers Are Effective in Several Types of Asthma

A number of agents developed to interrupt the 5-LO pathway are available in many countries around the world as treatments for asthma (Fig. 1). Initial studies with these drugs focused on their ability to decrease leukotriene production (as measured by urinary leukotriene production) (74) and inhibit bronchoconstriction induced by inhalation of leukotrienes such as LTD4 (75-79). Because all of these studies demonstrated that each of the leuko-triene modifiers had a substantial impact on either leukotriene synthesis or CysLT1 receptor-mediated bronchoconstriction, as well as on many of the mediators of inflammation produced in asthma by eosinophils, alveolar macrophages, and lymphocytes (80), these drugs were subsequently tested in cohorts of asthmatics in a variety of settings (1) laboratory-induced asthma, (2) asthmatic bronchoconstriction and airway inflammation, and (3) chronic persistent asthma.

Laboratory Induced Asthma

Laboratory-induced asthma includes asthma that is induced by challenge with cold air, exercise, aspirin, or antigen. Cold Air-Induced Asthma When asthmatic subjects hyperventilate cold, dry air, bronchospasm is often induced by a mechanism thought to be similar to that responsible for exercise-induced asthma. Israel and colleagues demonstrated that zileuton attenuated the bronchoconstrictor response to cold air (81). Similarly, Fischer et al. (82) demonstrated that regular treatment with zileuton for 13 weeks improved airway responsiveness to cold air-induced airway obstruction for as long as 10 days after completion of treatment, suggesting that inhibition of leukotriene generation can improve airway hyper-responsiveness. In addition, zafirlukast has been shown to similarly attenuate both cold-induced response as well as exercise-induced bronchoconstriction. These observations led to the proposal that the cooling and drying of airways provoked by these challenges results in...

Asthmatic Bronchoconstriction and Airway Inflammation

A major attribute of any asthma medication is its ability to counteract the spontaneous reversible bronchoconstriction that may develop in patients with mild to moderate asthma who withhold bronchodilator therapy. To assess the role of leukotrienes in the spontaneous airway narrowing of asthma, several leukotriene modifiers have been administered to patients with varying degrees of asthma, and spirometry has been performed. Each of the leukotriene modifiers has produced acute bronchodilatation and improvement in airway function within one to three hours. While the magnitude of bronchodilatation is often not as great as that with -agonist therapy, FEV1 is generally increased by 5 to 30 the bronchodilator effect is also greater in patients with greater degrees of airway obstruction. Furthermore, the effects of the leukotriene modifier were additive to the effect of the -agonist, suggesting that distinct contractile mechanisms are involved in each response (107-112). Because similar...

Chronic Stable Asthma

In addition to their anti-inflammatory effects and benefits in patients with a variety of lab-induced models of asthma, leukotriene modifiers have significant efficacy in patients with chronic persistent asthma, compared with placebo, both as monotherapy and as add-on therapy to other controllers. Multiple studies have shown that, when asthma patients who used inhaled p-agonists as their only asthma medication were treated with a leukotriene modifier (pranlukast, zafirlukast, montelukast, or zileuton), asthma improved such that they had improvement in airway obstruction, decreased need for rescue treatment with p-agonists, relief of asthma symptoms, and decreased frequency of asthma exacerbations that required systemic corticosteroid therapy (111,112,128,129). In studies of four to six weeks duration, patients with moderate asthma (mean FEV1 of 65 predicted) treated only with p-agonists were given placebo in a single-blind manner for a run-in period of 7 to 14 days, followed by an...

Efficacy for Treating Acute Symptoms from Asthma

The traditional role of theophylline as an acute intervention measure has changed with more aggressive use of inhaled p2-agonists and systemic corticosteroids. A controlled clinical trial of 44 adults seen for acute asthma in an emergency department showed no greater benefit from theophylline (as intravenous aminophylline) than placebo when added to vigorous use of inhaled b2-adrenergic agonist drugs and systemic corticosteroids (57). In patients with severe exacerbations requiring hospitalization, data on the value of adding theophylline are conflicting (58-61). In one study of 39 hospitalized adults, the addition of theophylline to inhaled albuterol (salbutamol) and oral prednisone was not beneficial (58). In contrast, another study of 21 adults treated with inhaled albuterol, intravenous methylprednisolone, and theophylline or placebo found that the theophyl-line-treated patients had greater improvement in FEV1 at 3 and 48 hours and needed rescue therapy with inhaled albuterol less...

Efficacy as Maintenance Therapy for Chronic Asthma

Theophylline has been repeatedly demonstrated to be effective as a single maintenance medication in the management of chronic asthma. The first studies of this in the early 1970s demonstrated that symptoms were markedly diminished, and need for intervention with measures to treat acute symptoms were virtually eliminated for most patients (14,15). Subsequent studies compared theophylline with alternative medications. Theophylline was associated with more asymptomatic days than cromolyn sodium (disodium cromoglycate) when both were used as monotherapy in patients with severe chronic asthma (16), although efficacy appeared similar in patients with milder asthma (62-64). Comparison with oral p2-agonists have shown clinical advantage for theophylline, especially for nocturnal symptoms (65,66). Although inhaled albuterol is far more potent for acute bronchodilatation than theophylline, a controlled clinical trial demonstrated that theophylline nonetheless provided more stable clinical...

Is there a relationship between GERD and asthma or chronic lung disease

Fifteen million Americans have asthma, and it is estimated that about 30-90 of asthmatics have reflux. Asthma is a lung disease characterized by muscle spasms in the airways of the lungs. When these muscles go into spasm and contract, it limits the ability of air to move in or out of the lungs and causes wheezing, shortness of breath, or coughing. This is treated usually with inhaled medications that relax the airways. Many factors can start an asthma attack, such as pollen and other allergens such as animal hair, cold air, noxious fumes, and stomach acid. Sometimes a chest cold caused by an infection can start or worsen asthma symptoms. Some people with asthma have symptoms of GERD, but many do not. A study of 199 asthmatics who had pH studies (see Question 69) conducted by Harding, Guzzon, and Richter, and published in Chest in 1999, showed that 72 had abnormal amounts of acid in the esophagus. Reflux makes asthma worse when aspirated stomach acid enters the lungs and burns the...

Indications for Theophylline

Medications for asthma include those used for intervention to relieve acute symptoms of asthma when they occur, and those used for maintenance to prevent symptoms of chronic asthma. The use of theophylline as intervention for acute bronchodilatation has largely been supplanted by the current generation of inhaled bronchodilators, such as albuterol, which are specific for p2-adrenergic agonist receptors and can safely be given in higher doses Table 3 Theophylline Dosage Guidelines for Children Beyond Early Infancya and Adults Who Have No Risk Factors for Decreased Theophylline Clearanceb Serum theophylline concentration These are based on the principle of beginning with about two-thirds of average doses and increasing slowly, only as tolerated, approaching but not exceeding average doses for age. aFor infants 6-26 weeks of age, the initial daily dosage is expressed by the regression equation dose (in milligrams per kilogram per day) (0.2) (age in weeks) + 5.0 this is 2 3 of the median...

Posttheophylline Phosphodiesterase Inhibitors

More selective PDE inhibitors have been under investigation for their antiasthmatic potential. Rolipram is a specific inhibitor of PDE 4 that did not match theophylline in anti-inflammatory effects, whereas a dual selective inhibitor of PDEs 3 and 4, zardaverine, exhibited greater effect in vitro (314). Another specific inhibitor of PDEs 3 and 4, identified as Org 20241, both relaxes airways smooth muscle and inhibits eosinophil activation in various in vitro systems to a greater degree than rolipram (315). However, a report examining theophylline and rolipram on antigen-induced airway responses in neonatally immunized rabbits demonstrated prevention of airway hyper-responsiveness following allergen aerosol from rolipram but not theophylline, although both inhibited eosinophil recruitment (316). Another agent, identified as CDP840, is a specific inhibitor of PDE 4 that was more active than rolipram in reducing antigen-induced bronchocon-striction and pulmonary eosinophilic...

Nedocromil for Asthma

As nedocromil is a newer agent when compared to cromolyn and comes in only a single form, there is less information to draw conclusions from. Most of the studies show a beneficial effect of nedocromil when compared to placebo. Children with grass pollen asthma responded better to nedocromil compared to placebo (121). In a study by Konig et al. (122), the use of nedocromil did not prevent viral-induced bronchospasm but did improve their recovery, overall symptoms, and PEFR on nedocromil. A third investigation that compared nedocromil to placebo resulted in an advantage to nedocromil with total symptom score reduction of 50 (123). In addition, significant improvement in daytime and nighttime asthma, morning and evening PEF, and use of rescue bronchodilators was shown with the regular use of nedocromil (124). Currently there is only one study comparing nedocromil to the use of ICS. Children treated with beclomethasone dipropionate had a significant improvement in nonspecific bronchial...

Antitussive And Antiasthmatic Activity

Passiflora incarnata was as effective as codeine phosphate in suppressing a sulfur-dioxide-induced cough in mice (Dhawan & Sharma 2002). Passionflower (100 mg kg) was also able to prevent dyspnoea-related convulsions in guinea pigs with acetylcholine-induced bronchospasm (Dhawan et al 2003b).

Systemic Corticosteroids in Asthma

The vast majority of patients achieve adequate asthma control with regular inhaled corticosteroids and bronchodilators. A subgroup will require additional therapy or combinations of treatment, but a small percentage of patients have refractory disease with poorly controlled symptoms, recurrent exacerbations, and or persistent airflow obstruction despite such treatment (1). The regular use of systemic corticosteroids may be required to achieve improvements in asthma control in these patients. Additionally, systemic corticosteroids remain the treatment of choice for the management of acute severe exacerbations of asthma. This chapter will discuss the pharmacology and mechanisms of action of systemic corticosteroids, review the evidence for their clinical effectiveness and adverse effects, and offer recommendations for their use in asthma. Corticosteroids are highly lipophilic molecules that are generally well absorbed from the gastrointestinal tract, resulting in systemic...

Medical Disorders Asthma

As noted previously, 20 of youth have two chronic disorders and 10 have three or more. Thus, finding a youth with one condition (e.g., a rheumatic disorder) does not mean that other disorders are not present. Asthma prevalence in children increased 3.6 in 1980 and 5.8 in 2003 (46). Asthma is one of the most common medical conditions among adolescents, and its prevalence has increased over the past few decades, including 46 increase in Australia, 4.3 in the United States, 34 in New Zealand, and 4.6 in Japan (47). Though research has produced improved medications for asthma treatment, asthma mortality has continued to increase throughout the world. For example, from the mid-1970s to the mid-1980s, there was an increase in asthma-related deaths for 5- to 34-year-olds of staggering proportions 34 increase in Japan, 17 increase in Singapore, and 111 increase in the United States (47). The causes of this increase in morbidity and mortality are unclear, but linked to the complex interaction...

Patient Candidates for Alternate Asthma Treatments

Because of the potential toxicity of some proposed alternate treatments for asthma, asthma patients who might be considered candidates for therapy with alternate agents are often the most problematic of asthma patients. These patients may fall into several subsets. First, there are patients who do respond to systemic corticosteroids, but are termed steroid dependent because they require chronic administration of systemic corticosteroids, often at doses that have the potential to cause significant side effects such as osteoporosis, cushionoid features, or glucose intolerance. Second, there are patients who are termed steroid resistant who, by definition, fail to respond to a 7- to 14-day course of daily prednisone as measured by less than a 15 improvement in morning prebronchodilator FEV1 following the glucocorticoid course (5). Furthermore, two types of steroid-resistant asthma have been defined. Type-I steroid resistant asthma is acquired and is associated with abnormally reduced...

Caveats in Interpreting Asthma Trial Data

In reviewing trials that attempt to assess the clinical efficacy of new, alternate, or experimental therapies for asthma, study results must be viewed with an awareness that the natural history of asthma is highly variable. Dykewicz et al. retrospectively reviewed the natural history of 40 patients who had been treated with inhaled steroids but still required systemic steroids (mean dose 11.7mg day prednisone) for at least one year (mean duration 6.2 years) (9). During 12 to 32 months of follow up, 25 tolerated discontinuation of oral steroids, and 7.5 tolerated significant reductions of oral steroids. Although 60 had no change in long-term steroid-dose requirements, one-third of these patients were able to discontinue prednisone for extended periods (mean 3.2 years) during follow up, only to again require steroid doses similar to the original requirements. Consequently, studies without placebo-control groups that report a reduction in oral-steroid requirements in association with use...

The Importance of Allergy in Asthma

There is a strong familial component to asthma, eczema, and rhino-conjunctivitis, the so-called atopic cluster. While this argues for a genetic component to asthma, the rapid increase in the prevalence of asthma means that something in the environment must be responsible. The current consensus is that environmental factors act on genetically susceptible individuals, stimulating the production of specific IgE antibodies against otherwise harmless environmental antigens, such as pollen, house dust mite, and animal dander proteins. Not everyone who develops IgE antibodies will go on to experience clinical symptoms. Indeed, only half of the people with detectable levels of antibody against grass pollen will have any sort of hay fever. Nevertheless, the more IgE antibody someone has, the more likely they are to have associated clinical symptoms. Usually, there is a progression of allergic disease, sometimes termed the allergic march, in which children first suffer with atopic eczema, then...

IIISIT to Prevent Asthma

Specific immunotherapy may modify the natural history of asthma in children, who are known to be atopic but have not yet developed asthma. Studies from the 1960s and 1970s indicate that between 5 and 10 of atopic children and young adults with allergic rhinitis will develop asthma symptoms each year, although the epidemiological context is changing and these data will need updating (29). In children with allergic rhinitis and a limited range of sensitivities, SIT with house dust mite extract has been shown to reduce the probability of developing new sensitivities (i.e., new positive skin tests to allergens other than the one used for therapy) (30). An ongoing major multicenter study is assessing whether SIT is able to prevent allergic children aged 7 to 13 years from going on to develop asthma. After three years of therapy 28 fewer children had asthma symptoms compared to the control group, and this difference has been maintained up to five years, suggesting that SIT does indeed...

IVSIT to Manage Established Asthma

Immunotherapy has been widely used to treat allergic asthma, but with the introduction of more effective inhaled therapies and increased concerns about the side effects of SIT, questions have been raised about the place of SIT in managing asthma. The efficacy of SIT in adult asthma has been assessed in many trials over the last 50 years. Some of the earlier studies are difficult to interpret, because poor quality allergen extracts were used or the studies were poorly designed. A Cochrane review of allergen immunotherapy for asthma considered 75 trials published up to June 2001, including all available randomized, controlled trials that had used SIT to treat asthma and had reported at least one clinical outcome (32). These trials included nearly 3200 patients with asthma. Thirty-six of the trials were of SIT for house mite allergy, 20 for pollen allergy, 10 for animal dander allergy, two for mold allergy, one for latex allergy, and six for mixed allergens. Unfortunately, concealment of...

Comparison of SIT with Other Types of Treatment for Asthma

Most clinical trials of SIT for asthma have compared SIT either with historical controls or with a matched group treated with placebo. Very few studies have compared specific SIT with conventional management of asthma using allergen avoidance measures and conventional inhaled or oral drugs. A recent study of SIT in asthmatic children receiving conventional drug therapy found Work from the 1950s and 1960s using mixed allergen extracts suggested that SIT may increase the rate of remission for children with asthma, and may also reduce the severity of symptoms in those who remain symptomatic (36). In contrast, a study that investigated withdrawal of therapy found rapid recurrence of asthma symptoms after stopping SIT, although there was more sustained relief for rhinitis symptoms (37).

Risks of Allergen Immunotherapy in Asthma

The main issue that prevents the widespread adoption of SIT for asthma is the risk of serious adverse reactions. In the United Kingdom, between 1957 and 1986,26 fatal reactions due to SIT were reported to the Committee on Safety of Medicines (38). In 17 of the fatal cases, the indication for SIT was documented, and 16 of these 17 patients were receiving SIT to treat their asthma. Similarly, in the American Academy of Allergy Asthma and Immunology confidential inquiry into SIT-associated deaths, asthma appeared to be the mode of death in virtually all the fatal cases (39). In those where asthma was not cited as a contributory factor, bronchospasm was a cardinal feature of the clinical course of the anaphylactic reactions that led to death. The incidence of systemic reactions in patients receiving SIT for asthma varies between series and has been reported to range from 5 to 35 . The central issue in using safety as an endpoint is to recognize that all treatments carry risks. Where...

Near Fatal Asthma and Acute Asthma Onset

A category of asthma severity commonly investigated and reported in the literature is the ''near-fatal asthma'' (NFA) attack. This entity was originally proposed as part of the investigation of increases noted in asthma mortality from the 1970s on (42). Cases of NFA are more prevalent than fatalities, yet evidence suggests that these two groups may share common features, and that the former may be a useful epidemiologic marker for the latter (43). NFA is most commonly defined as asthma cases that require ventilatory assistance (42,44,45), but the term has been used to describe patients with hypercarbia, frequent hospitalization, or even severe respiratory symptoms with altered level of consciousness (46,47). Clinical characteristics that have been commonly associated with NFA include recurrent admissions, prior need for ventilatory assistance, frequent p-agonist use, and an increased incidence of psychosocial problems (48). Variation in inclusion criteria among studies on NFA, the...

Pharmacotherapy for Asthma Stepwise Approach

The NAEPP report emphasizes that the stepwise approach should be used to guide but not replace physician decisions regarding treatment of individual patients (2). In rating severity, a patient should be assigned to the most severe step if any one feature of the higher severity category is present. Physicians should follow the strategy of achieving control as quickly as possible (e.g., treating with a burst of oral prednisone, if indicated) and then stepping down to the least medication needed to maintain long-term asthma control. As already mentioned, it is essential to provide patient education in self-management and control of environmental triggers (e.g., allergens). Severely asthmatic patients with acute exacerbations or hospitalizations or poor perception of asthma symptoms should be trained in the use of serial PEFR measurements to aid in early recognition of asthma flare-ups. This should involve intensive education regarding self-management of acute exacerbations in which...

Euphorbia hirta L Euphorbiaceae Asthma Weed

Genital Lesion Lasting Weeks

Traditional Medicinal Uses The whole plant is decocted for athlete's foot, dysentery, enteritis, fever, gas, itch, and skin conditions. 3 It is also regarded as anodyne, depurative, diuretic, lactogogue, purgative, and vermifuge. The plant is used for asthma, bronchitis, calculus, colic, cough, dyspnoea,

Drugs That Alter Theophylline Disposition

Most commonly used drugs do not interact adversely with theophylline. Amoxicillin (262,263), ampicillin with (264) or without sulbactam (265), cefaclor (266,267), metronidazole (268), co-trimoxazole (269), tetracycline (270), azithromycin (271), terfenadine (272), and montelukast (data on file, Merck Pharmaceuticals) have been specifically studied and have no effect on theophylline clearance, nor is there evidence that other related medications have drug interactions with theophylline. On the other hand, while the quinolone antibiotics ofloxacin (273,274), norfloxacin (275,276), lomefloxa-cin (277-281), and flosequinan (282) have little or no effect on theophylline clearance, ciprofloxacin, enoxacin, and perfloxacin do slow theophylline elimination. Similarly, the H2 blockers famotidine (283), ranitidine (284), and nizatidine (285) have no effect on theophylline clearance, while cimeti-dine, uniquely in that class, can substantially slow theophylline clearance. Controlled clinical...

Physiologic Factors Associated with Alteration in Theophylline Disposition

Theophylline Dose Serum Level

Total body clearance, the product of volume of distribution and elimination rate constant, quantifies theophylline removal from the body. While intrapatient variability in clearance is small (223,229), interpatient variability is large and appears to be from differences in the rate of hepatic biotransformation, which changes with age, concurrent illness, smoking, pregnancy, aberrations in diet, and intake of other drugs. The volume of distribution is a somewhat larger fraction of body weight in infancy and varies inversely with body fat. However, the major variable of the two components of clearance is the elimination rate, often expressed as a half-life of elimination. Because of immature hepatic enzymes, metabolic clearance of theophylline is very slow in the neonate, and even more so in the premature, with elimination half-lives averaging greater than 24 hours. Consequently, dosage requirements are markedly reduced in neonates (194,255) and increase during the first year of life...

AntiIgE Therapy for Asthma

Allergic diseases, such as allergic asthma, are hypersensitivity reactions initiated by immunological mechanisms (1,2). They are usually mediated by IgE antibodies, triggering an inflammation characterized by an increase in production of Th2-type cytokines at a mucosal surface, the interface between the external and the internal environments. Allergic diseases usually occur in atopic individuals who are genetically predisposed to producing IgE antibodies in response to low doses of general environmental allergens, e.g., pollens, mites, and danders. Although allergies mediated by other immuno-globulins (e.g., IgG-immune complexes that can activate complement) or lymphocytes (e.g., allergic contact dermatitis to chromium and nickel) also exist, the major part, if not all, of allergic asthma is IgE mediated. The cross-linking of mast cell basophil membrane cell-bound IgE antibodies by allergen results in the release of inflammatory mediators that are responsible for the signs and...

Cromolyn for Asthma

Several studies have shown that ICS are more effective than cromolyn in patients with severe asthma (88-90). However, some studies in mild to moderate asthmatics have shown either comparable efficacy (91-93) or an even better response to ICS (94,95). On the other hand, the addition of cromolyn to ICS failed to show any beneficial effect (96). A more recent review of 24 placebo-controlled trials of cromolyn concluded, ''there is insufficient evidence for a beneficial effect of CS as maintenance treatment in children with asthma.'' Further review of this study shows that cromolyn is more effective in older children (97). In addition, a recent review reported no significant difference between DSCG and placebo in children with asthma (98). The use of cromolyn versus placebo administered via face mask with spacer device in 167 children aged one to four years found no difference in the primary outcome measure of symptom-free asthma days between the two groups (99). Long-term studies with...

Diagnosis of Asthma

The schema presented for asthma classification and diagnosis is particularly relevant. The GINA document emphasizes the importance of utilizing lung-function measurements in the diagnosis of asthma. The GINA guideline highlights questions that can be used in a clinical setting, which are from the International Union Against Tuberculosis and Lung Disease questionnaire, a validated instrument that has been employed in epidemiologic studies (6). Traditionally, a diagnosis of asthma is confirmed by a 12 or greater improvement in FEVi after inhalation of a p-agonist bronchodilator or after an interval of treatment with systemic or inhaled glucocorticoids. The FEV1 has been considered the premier endpoint to measure both short-term and long-term asthma clinical trials. However, single measurements of lung function can underestimate asthma severity status unless other symptoms or morbidity indicators are considered, including numbers of acute asthma exacerbations, rescue bronchodilator...

Pharmacological Activities Potentially Relevant for Asthma

Although traditionally classified as a bronchodilator and initially used primarily for acute bronchodilatation, the ability of theophylline as maintenance therapy to control chronic asthma has always appeared disproportionately greater than was explainable by its modest degree of bronchodilator activity alone (14-22). In addition to bronchodilatation, theophylline has broncho-protective (23-26), anti-inflammatory (27-30), and immunomodulatory (22) effects that potentially contribute to its efficacy as a maintenance medication for controlling chronic asthma. Theophylline attenuates airway responsiveness to histamine (23), metha-choline (23), allergen (27), sulfur dioxide (24), distilled water (25), toluene diisocyanate (31), and adenosine (32). While the degree of attenuation is modest for most of these bronchoconstrictors, theophylline can completely inhibit airway responsiveness to exercise at serum concentration of > 15 mg mL (26), the upper half of the 10-20 mg mL range shown to...

Cromolyn and Nedocromil Comparison Trials

A few studies have compared cromolyn to nedocromil, whereas others have compared cromolyn, nedocromil, and ICS. No differences in PFT could be found in 195 children treated with cromolyn, nedocromil, or ICS (131). Similarly, there were no differences found in efficacy when comparing cromolyn to nedocromil in another paper (132). Review of the Cochrane database also could find no difference in efficacy between DSCG and nedo-cromil during the post-exercise pulmonary functions in either the maximum percent decrease in FEV1 or complete protection (133). An additional study by Lal et al. (134) reported a 50 reduction of ICS dose with the addition of cromolyn or nedocromil in adults. They reported that nedocromil was more effective than cromolyn in symptom control and reduction of bronchodilator use. Orefice et al. found nedocromil superior in controlling symptoms however, both cromolyn and nedocromil were effective with decreasing non-specific bronchial hyper-reactivity and the need for...

Acute Severe Asthma Status Asthmaticus in Adults

Clinical studies suggest that b2-adrenergic agonists are more effective bronchodilators in the setting of acute severe asthma, and that an anticholinergic agent should not be used as the sole initial bronchodilator. The question arises whether an anticholinergic agent can add to the bronchodilatation achieved by the adrenergic agent. Rebuck et al. (33) found that the combination of 500 mg nebulized ipratropium with 1.25 mg nebulized fenoterol (a p2-adrenergic agent available outside the United States) resulted in significantly more bronchodilation over the first 90 minutes of treatment than either agent alone. Moreover, patients with more severe airway obstruction obtained the greatest benefit from the combination. Other studies have addressed this same question and a meta-analysis (34) of 10 such studies (total of 1377 patients) concluded that the addition of ipratropium reduced hospital admissions (relative risk 0.73) and increased FEV1 by 7.5 (on average 100 mL, 95 CI 50-149 mL)...

Biologic Effects of Leukotrienes Rationale for a Role in Asthma

Since elucidating the structure and biosynthetic pathway of leukotrienes, researchers have further demonstrated their potency in smooth muscle constriction in both human and animal models, in vitro and in vivo, and have shown that 5-LO products stimulate smooth muscle proliferation (37-39). For example, inhaled LTC4 and LTD4 resulted in potent airway obstruction as manifest by decreased specific airway conductance (SGaw) (40), and Bisgaard et al. (41) demonstrated that asthmatic subjects were 100 to 1000 times more responsive to LTD4 than controls. Subsequent studies demonstrated that prior inhalation of leukotrienes caused an increase in airway responsiveness to both histamine and methacholine that lasted as long as one week. 5-LO products may also cause tissue edema (42,43) and stimulate smooth muscle proliferation (44-46) as well as eosinophil and neutrophil recruitment and activation (47-50). Invoked as causative agents in a host of inflammatory conditions such as inflammatory...

Cromolyn for Allergic Rhinitis

In recent years, the one airway hypothesis linking disease and therapy in the lung and nose simultaneously suggests a need to briefly review the effect of the chromones on nasal allergy. Intranasal cromolyn is available over the counter as an aqueous preparation topical spray. Several studies have reported that intranasal cromolyn is superior to placebo in the treatment of seasonal allergic rhinitis (SAR) (5). In particular, a decrease in mouth breathing, nasal congestion, rhinorrhea, postnasal drip, and sneezing in 66 patients treated with intranasal cromolyn for ragweed rhinitis was observed (142). Similarly, a decrease in rhinitis symptoms and, in this case, ocular symptoms, was observed in 88 patients treated with cromolyn for pollen-induced SAR (143). A decrease in rhinitis symptoms measured by the average daily rhinitis symptom score resulted in decreased antihista-mine use with cromolyn in a small study of 47 patients (p < 0.01) (144). Perennial allergic rhinitis symptoms...

Future Prospects of Asthma Pharmacotherapy

Although drug therapy is crucial in the management of patients with asthma, there is a huge variation in drug responses between individual patients. In asthmatics, this variation may be due to differences in disease severity, drug adherence, environmental exposures, or age, but genetic factors may account for 60 to 80 of the heterogeneity in treatment responsiveness. Pharmacogenetics is the study of the contribution of these genetic differences among individuals to the variability in the responses to pharmacotherapy. Until now, physicians are unable to predict in which patients a drug will work well and in whom not. Identifying the genetic Recently, genetic polymorphisms in the 5-lipoxygenase (5-LO) gene and leukotriene C4 (LTC4) synthase gene have been described (91-93). Moreover, it was found that asthma in carriers of these genetic variants of the 5-LO pathway had a diminished response to treatment with antileu-kotriene drugs, indicating a pharmacogenetic effect of these genetic...

What Is the Role of Leukotriene Modifiers in the Treatment of Asthma

On the basis of their relative effectiveness in mediating asthma symptoms and maintaining lung function, their comparative efficacy with respect to other asthma treatment modalities, their excellent safety profile, and most important their ease of administration, each of the leukotriene modifiers has earned an important place in the treatment of asthma. But where do these medications fit in the complex treatment paradigms that physicians use in treating this disease In addition to their clear benefits in patients with aspirin-sensitive asthma, exercise-induced asthma, and cold-sensitive asthma, and their synergistic benefits in allergen-associated asthma, these drugs may be used as first-line therapy for mild persistent asthma and as add-on treatment for those patients whose asthma is not controlled by inhaled corticosteroids. First-Line Asthma Treatment First-line asthma treatment is medication given to a patient whose asthma is no longer controlled by rescue use of inhaled...

Dosage for Maintenance Therapy of Chronic Asthma

The interpatient variability in clearance, combined with the narrow therapeutic index of theophylline, results in an overlap of therapeutic and potentially toxic doses, i.e., doses optimal for some patients may be excessive for patients with slower clearance. Furthermore, initiation of therapy with theophylline may be associated with mild, transient caffeine-like side effects such as nausea, headache, nervousness, and insomnia even at low serum concentrations (96). These symptoms can generally be avoided or minimized by beginning with low doses, no more than about two-thirds of average dosage for age and size, and increasing only slowly as tolerated at intervals no more frequent than three-days, approaching but not exceeding average doses for age (Table 3).

Asthma

Asthma is the most common chronic illness seen in childhood, affecting 5 to 15 percent of children in the United States, approximately 3 million children younger than eighteen years of age. One-third of these children have severe asthma. Over the last twenty-five years, there has been an increase in the prevalence of asthma. Although part of this may be attributed to physicians diagnosing asthma earlier in children, there still seems to be a real rise in the number of children worldwide with asthma. In the United States, African-American children are more likely to have asthma and more severe instances of the disease compared to Caucasian children. African-American children under four years of age are hospitalized four times as often for their asthma. Crowded inner city living also has been shown to increase a child's likelihood of having asthma, regardless of race. The inner city environment has particles or allergens such as air pollutants that sensitize these children to develop...

Nocturnal Asthma

Symptoms of asthma occur more frequently during the night than during the day 7 . Furthermore, some circadian changes seem to be associated with worsening nocturnal asthmatic symptoms. Cortisol levels are lowest in the middle of the night, increasing and peaking in the early morning 23 while higher levels of histamine (a mediator of bronchoconstriction) coincide with greater bronchoconstriction during sleep time 24 . Since bronchoconstriction and exacerbation of nocturnal asthmatic symptoms vary in a circadian fashion, chronotherapies have been studied for asthma, employing theophylline, b2-agonists, anticholinergic drugs, and corticosteroids. Sustained release formulations of theophylline are administered in the evening to alleviate airways obstruction and nocturnal asthma 25 . Oral administration of corticosteroids at 8 00 a.m. and 3 00 p.m. was more effective in controlling nocturnal asthma than the same doses administered at 3 00 p.m. and 8 00 p.m. 26 .

Cromolyn

At physiological pH both cromolyn and nedocromil are small, water-soluble, highly ionized compounds with negligible fat solubility that are poorly absorbed from the gastrointestinal (GI) tract (8). These properties are responsible for the inability of these drugs to enter the intracellular space of cells leading to their excretion in the urine (80 ) and feces after biliary secretion (20 ) (8). CS binding to plasma proteins is poor and reversible, which accounts for the extremely low incidence of adverse drug interactions (7). Less than 1 of an oral dose of CS is absorbed from the gastrointestinal tract, but approximately 7 to 9 of an inhaled dose reaches the systemic circulation with peak plasma levels achieved 10 to 15 minutes after inhalation (9). Relatively rapid clearance occurs from the lung with up to 75 of the inhaled dose being removed by two hours. Only 2 of the inhaled dose may remain in the lung for 24 hours (7-9). Plasma half-life is less than two hours and is nearly...

Intermittent Asthma

If over a period of at least three months a patient experiences less than once a week symptoms of cough, dyspnea, or wheezing, the patient has intermittent asthma. Nocturnal asthma symptoms are rare and occur less than twice a month. The patient is asymptomatic in between exacerbations and has a normal lung function (peakflow as well as FEVj). No maintenance treatment with a controller medication is recommended for intermittent asthma. Patients with intermittent asthma who experience rare but severe exacerbations, however, should be treated as having moderate persistent asthma (see section Combination Therapy as Maintenance Treatment of Moderate to Severe Persistent Asthma).

Persistent Asthma

If a patient experiences symptoms more than once a week over a three-month period, or has nocturnal asthma symptoms more than twice a month, the patient has persistent asthma. Patients with persistent asthma require controller medication every day (Table 2). Monotherapy as Maintenance Treatment of Mild Persistent Asthma Inhaled Corticosteroids ICS are the cornerstone therapy for patients with persistent asthma at all levels of severity, and are considered the most effective anti-inflammatory therapy. Numerous studies have demonstrated that treatment with ICS decreases the pathological signs of airway inflammation in asthmatics (21-23), reduces the airway hyper-responsiveness (24), and improves lung function. More importantly, both symptoms and the frequency and severity of exacerbations are reduced in patients with persistent asthma treated with ICS (25,26). Even in patients with mild persistent asthma of recent onset, once-daily treatment with low-dose budesonide significantly...

Atopy And Asthma

Vitamin C is the major antioxidant present in the extracellular fluid lining of the lung, where it protects against both endogenous free radicals (produced as a by-product of inflammation) and environmental free radicals (such as ozone in air pollution). According to many epidemiological studies, dietary intake of vitamin C-rich foods or serum ascorbate is associated with improved lung function in both asthmatic and normal subjects (Devereux & Seaton 2005). Despite a theoretical basis for its use in lung diseases such as asthma, its value in this disease is controversial. A 2001 Cochrane review of three studies concluded that current evidence is insufficient to recommend a specific role for vitamin C in the treatment of asthma and that a large-scale RCT is required to clarify its role (Kaur et al Alternatively, the evidence for its use in exercise-induced asthma appears stronger, as three human studies have produced positive results when vitamin C was used as pretreatment (Cohen et...

Nedocromil

Nedocromil belongs to the structural class of pyranoquinolines (3). As noted above nedocromil is water soluble, rapidly absorbed from the lung, has negligible fat accumulation, and has minimal absorption from the GI tract. Similar to CS, adverse drug reactions occur infrequently due to the low to moderate protein binding capacity of nedocromil. Drugs that do bind proteins readily are not displaced by nedocromil, resulting in no changes in half-life or clearance of these other compounds. Nedocromil has only one available vehicle of medication-inhalation, a 2 mg per actuation MDI, with < 10 deposition of the total dose in the lung. The peak plasma concentration is reached at 15 minutes in asthmatic patients and the drug is excreted after pulmonary absorption in the urine and GI tract from swallowing (90 ) and biliary excretion (7,10).

Bronchodilators

Bronchodilators are drugs that open the airways in the respiratory tract. They are widely prescribed as pills and aerosol inhalers to patients with asthma to relieve the wheezing and difficulty in breathing characteristic of that disease. Most of these drugs work by stimulating the sympathetic nervous system, which regulates the muscular walls of the bronchial tubes. As a result, in addition to their desired effect, they commonly cause stimulation, anxiety, jittenness, and insomnia. Patients often dislike these side effects but have no alternatives to the drugs if they want to breathe. Another problem with the stimulant bronchodilators is their strong tendency to cause dependence. When the effect of a dose wears off, bronchial constriction increases as a reaction to the drug, making further doses necessary. Asthmatics frequently m- hide bronchodilators throughout the day, in addition to taking them regularly by mouth. This frequency of use increases risks of addiction and mood change....

Therapeutic Approach Nonpharmacologic Considerations

The NHLBI report in 1997 is very similar to the GINA document in emphasizing four components of asthma management, including (i) the use of objective measures of lung function to establish the diagnosis, assess asthma severity, and monitor treatment responses (ii) control both allergic and non-allergic factors that trigger asthma symptoms and exacerbations (iii) pharmacologic treatment plans aimed at controlling airways inflammation and treating exacerbations and (iv) education programs directed at patients (including self-management skills) and families, as well as health care providers. In addition to recommending asthma drug regimens tailored to asthma severity status, the GINA guidelines stress the importance of non-pharmacologic management and emphasize the need for global initiatives to improve asthma education. Such efforts are directed at improving patient compliance with optimal recommended treatments, which is generally assumed to be the key determinant of favorable...

Pharmacologic Treatment Recommendations

Because both the NAEPP and GINA guidelines regarding pharmacotherapy are evidence based, recommendations pertaining to asthma management are often accompanied by ratings of the relative quality of scientific evidence from which they are derived. The GINA document has proposed an asthma severity classification that closely resembles those of the NHLBI guidelines (Table 4). Levels A-D categories of evidence are defined as Level A recommendation that is based upon substantial numbers of randomized controlled clinical trials and a rich body of evidence Level B recommendation based upon limited numbers of randomized controlled trials Level C recommendations based upon observational studies and Level D recom-mendations that are based upon the lowest level of evidence and derived strictly from expert opinion. In contrast to the NAEPP reports, the 2002 GINA report is more diligent about assigning evidence ratings for specific recommendations. Criteria for this category are presented in Table...

Safey Issues Related to Inhaled and Systemic Corticosteroids

The NHLBI document states that inhaled corticosteroids are the most effective therapy for long-term control of mild, moderate, and severe persistent asthma and are well tolerated at recommended dosages. The overwhelming evidence demonstrating their efficacy far outweighs the small risks of adverse effects. Local adverse effects of ICS include oral candidiasis, dysphonia, reflex cough, or bronchospasm with inhalation. Spacer devices are recommended to prevent dysphonia and oral candidiasis. The key recommendations for reducing the potential adverse effects of ICSs are (i) administer ICS drugs with holding chambers or spacers (ii) patients should be instructed to rinse their mouths with tap water after each dose (iii) use the lowest effective doses (iv) consider adding a LABA to a low or medium dose of ICS rather than increase ICS dose (v) monitor growth in children and (vi) recommend supplemental calcium (1000-1500 mg day) and vitamin D in postmenopausal women receiving ICS therapy (2).

Impact of Guidelines on Physicians Prescribing Patterns

Stafford et al. (29) reported data that reflected prescribing patterns of office-based U.S. physicians. This information was obtained from the National Disease and Therapeutic Index, which tracked trends from 1978 to 2002 in the frequency of asthma visits and patterns of asthma prescriptions. Although annual visits for asthma in the United States increased gradually from 1978 to 1990, the number of physician encounters for asthma had stabilized since 1990. At the same time, use of controller medication increased eight-fold between 1978 and 2002. Utilization of ICSs represented the largest increase in controller medications. An increase was also noted in the ratio of controller-to-reliever medication prescribed. Thus, these data indicate that patterns of asthma pharmacotherapy had changed over 25 years and are perhaps responsible for stabilization in numbers of patient visits since 1990. These prescribing patterns were likely influenced by dissemination of evidence-based guidelines to...

Use of Long Term Antiinflammatory Agents

When the NHLBI guidelines were constructed and released in 1991, it was widely assumed that anti-inflammatory controller agents must be initiated early (even in mild persistent asthma) to prevent progressive decline in lung function that would ensue due to unmitigated airways inflammation and subsequent remodeling. This theory was based on retrospective evidence in childhood asthma studies showing that more severe and irreversible airway obstruction was significantly associated with a delay in initiation of an ICS. More recent long-term prospective data from the Childhood Asthma Management Program (CAMP) study collected in asthmatic children treated for five years have failed to show significant differences between placebo, cromolyn, and ICS treated patients in changes in FEV1 (30). However, the ICS (budesonide) treated group had fewer hospitalizations, urgent visits for asthma, and reduced airway responsiveness compared to nedocromil. Accelerated decline in lung function was...

Novel Approaches for Improving Guideline Directed Treatment Outcomes

Green et al. recently compared treatment outcomes in a group of asthmatics actively managed by using serial sputum eosinophils counts to assess treatment response versus a group managed according to the British asthma treatment guidelines (51). The sputum-managed group had significantly fewer severe asthma exacerbations and asthma hospital admissions than did patients in the guideline managed group, despite the fact that there was no difference in mean doses of ICSs or oral corticosteroids between groups. A Canadian study evaluated the effectiveness of trained pharmacists in providing asthma education and monitoring compliance (52). Pharmacists participated in providing either enhanced care (asthma education regarding medications, triggers, and self-monitoring) or usual care to 631 asthma patients. After one year, compared to patients receiving usual care, the enhanced care group experienced a 50 reduction in symptom scores, an 11 increase in peak-flow readings, reduced days off work...

Clinical Use in Adults

Inhaled corticosteroids are established as the most effective initial antiinflammatory treatment for asthmatics with persistent symptoms. The use of LABA monotherapy instead in such patients leads to a loss of asthma control, e.g., there is increased airway inflammation and exacerbation rates for patients treated with salmeterol monotherapy compared to ICS mono-therapy (100). An alternative strategy is to use LABA as an additional therapy in patients who are symptomatic despite taking ICS. Additional LABA therapy in this context has been shown to improve lung function and reduce exacerbations (58,101,102). Before the introduction of LABA, it was common for the dose of ICS to be increased in such patients. However, this can have disappointing results as the dose-response curve for these drugs is relatively flat for the linear segment (103). Using LABA as additional therapy offers advantages over increasing the dose of ICS LABA provide an alternative mechanism of action (sustained...

Clinical Use in Children

LABA are known to have similar bronchodilator and bronchoprotective effects in children (130,131) compared to adults. The key issue in clinical practice is whether they should be used in the same way as in adults. It is no surprise that just as in adults LABA alone are less effective than low doses of ICS for the long-term control of asthma in children (132,133). Interest has therefore focused on the potential benefits of the addition of LABA to ICS regimes in children. In mild-asthmatic children, the addition of salmeterol to ICS improves lung function (134). Similar findings have been demonstrated for children with more severe asthma taking higher ICS doses (135). These results provided the impetus for a similar study design to those conducted in adults, i.e., a comparison of adding in a LABA to doubling the dose of ICS (136). Children with moderate asthma (mean FEV1 86 at entry) were randomized to receive either BDP 400 mg day, BDP 400 mg day plus salmeterol, or BDP 800 mg day for...

Influence of Genotype on p2Agonist Effects

The importance of these genotypes has been assessed in asthma in vivo. The gly-16 genotype is associated with a reduced bronchodilator response both in children (142) and adults (143). It has been proposed that these findings are due to excessive endogenous p2-AR down-regulation in subjects with the gly-16 genotype, so that inhaled p-agonists have less effect (144). Tan et al. (84) demonstrated that the gly-16 genotype is associated with increased bronchodilator tolerance after regular dosing with formo-terol (145). However, the sample size was small, with only four homozygous arg-16 subjects. These findings were not replicated using salmeterol in a placebo-controlled crossover study involving 20 subjects 10 glu-16 homozygotes and 10 arg-16 homozygotes (146). There was no influence of genotype on bronchodilator response or bronchoprotection after two-weeks treatment. A lack of association between genotype (either at position 16 or 27) and the degree of bronchoprotection was also...

Autonomic Control of Airways

In humans, almost all of the efferent autonomic nerves in the lungs are branches of the parasympathetic system derived from the vagus nerve, and are cholinergic in action (4). Branches of the vagus nerve travel along the airways and synapse at peribronchial ganglia with short postganglionic nerves, which supply airway smooth muscle cells, mucous glands, and possibly the ciliated epithelial cells, predominantly in the central airways. The release of acetylcholine from varicosities and terminals of the postgan-glionic nerves activates muscarinic receptors, thereby stimulating smooth muscle contraction, releasing mucus from mucous glands, and possibly accelerating ciliary beat frequency. At rest, a low level of cholinergic, vagal (bronchomotor) tone can be demonstrated in animals. This level of choli-nergic activity can be augmented by a variety of stimuli through neural reflex pathways (Fig. 1), resulting in rapid bronchoconstriction and release of mucus from airway mucous glands....

Muscarinic Receptor Subtypes in Airways

This scheme has clinical implications. Traditional anticholinergics are not selective for muscarinic receptor subtypes and may, therefore, be suboptimal. This provides an opportunity for the development of anticholinergic agents that selectively inhibit Ml and M3 receptor subtypes but spare the M2 receptor. Additionally, M2 receptors are selectively damaged by certain viruses as well as by some eosinophil products, which may contribute to the broncho-spasm associated with viral infections and asthma, respectively (12,13).

Protection Against Specific Stimuli

The protection afforded by anticholinergic agents against specific broncho-spastic stimuli in a research setting has been reviewed (3). When given in advance of bronchospastic stimuli, anticholinergic agents provide variable degrees of protection. Protection is more or less complete against cholinergic agonists such as methacholine. In asthmatics, they can prevent bronchos-pasm induced by -blocking agents and by psychogenic factors. They provide only partial protection against bronchospasm due to most other stimuli, e.g., histamine, prostaglandins, nonspecific dusts and irritant aerosols, exercise, and hyperventilation due to cold, dry air in asthmatic subjects (22,23). Against most of the latter stimuli, adrenergic agents usually provide greater protection. Ipratropium has no prophylactic effect against leukotriene-induced bronchoconstriction (24).

Acute Exacerbations of COPD

Four studies comparing the efficacy of bronchodilators in acute exacerbations of COPD have failed to discern a difference among adrenergic agents, Figure 5 Increase in FEVi of 15 patients with asthma (left panel) and 15 patients with chronic bronchitis (right panel). Abbreviations P, placebo I, ipratropium 40 mg MDI F + T, fenoterol 5 mg plus oxtriphylline 400 mg oral. Source From Ref. 52. Figure 5 Increase in FEVi of 15 patients with asthma (left panel) and 15 patients with chronic bronchitis (right panel). Abbreviations P, placebo I, ipratropium 40 mg MDI F + T, fenoterol 5 mg plus oxtriphylline 400 mg oral. Source From Ref. 52.

Effects on Sleep Quality

Sleep disturbance is common among patients with chronic bronchitis and asthma. Sleep disturbance in children with asthma is associated with psychological problems and impairment of memory (59). Among patients with COPD, 41 reported at least one symptom of disturbed sleep (60), possibly contributing to nocturnal oxygen desaturation, the development of pulmonary hypertension, polycythemia, and cardiac arrhythmias (61,62). A randomized double-blinded study involving 36 patients with moderate to severe COPD showed that ipratropium increased total sleep time, decreased the severity of nocturnal desaturation, and improved the patient's perceptions of sleep quality (63).

Clinical Recommendations

The use of anticholinergic bronchodilators should be limited to the poorly absorbed quaternary forms, e.g., ipratropium, oxitropium (where available), and tiotropium, administered by inhalation. They are sometimes useful in stable asthma as adjuncts to other bronchodilator therapy, and have a demonstrated role in combination with adrenergic agents in the treatment of acute severe asthma, but cannot be recommended as the sole broncho-dilator for the latter condition. Their principal indication is the long-term management of stable COPD, where they are probably the most efficacious bronchodilators. Because of their slow onset of action they are best used on a regular, maintenance basis, rather than p.r.n. The usual dose of ipratropium, two puffs of 20 mg each, may be adequate in asthmatics but is probably suboptimal for many patients with COPD (82) and can safely be doubled or quadrupled (83).

Reduction in Bronchial Responsiveness

It is well recognized that long-term treatment with ICS leads to a reduction in bronchial hyper-responsiveness (BHR) to different stimuli, including histamine, methacholine, allergen, and exercise (12,13). This occurs within a few weeks of starting treatment, with continued improvement over a period of months (14). For asthmatic individuals, this response means that a lesser degree of bronchoconstriction occurs when exposed to provoking stimuli in their daily lives. On a population level, it indicates that the widespread use of ICS will result in a significant reduction in the proportion of severe asthmatics within a community (15) (Fig. 2). Figure 2 A reduction in bronchial hyper-responsiveness through the use of inhaled corticosteroid therapy will lead to a marked reduction in the proportion of severe asthmatics within an asthmatic population. Source From Ref. 15. Figure 2 A reduction in bronchial hyper-responsiveness through the use of inhaled corticosteroid therapy will lead to a...

Clinical Efficacy

Long-term clinical trials have shown that the regular use of ICS leads to a reduction in symptoms such as nocturnal wakening, a reduced requirement for p-agonists, improved lung function, a reduction in the frequency of severe exacerbations, including hospital and intensive care unit (ICU) admissions, and mortality (1,19-22). Importantly, ICS represent the only therapeutic agents used in the long-term management of asthma that reduce the risk of life-threatening attacks, including those leading to hospital or ICU admission (20,23-26), and those that lead to a fatal outcome (2123,27,28). From a public health perspective, it is these properties that form the basis of the recommendations for the widespread use of ICS in asthma and as such represent the greatest opportunity to reduce the global burden of asthma.

Clinical Outcome Measures

The first major meta-analysis of this kind was based on placebo-controlled dose-response studies of the ICS FP in adults and adolescents with asthma (34). This demonstrated that for different outcome measures, including lung function, symptoms, p-agonist use, and exacerbations, at least 90 of the maximum efficacy can be achieved with a dose of FP of around 200 mg day (Fig. 3). In moderate to severe adult asthmatic patients the maximum effect was achieved with a dose of FP of around 500 mg day. This meta-analysis challenged the dogma that existed at the time that higher doses were required to achieve the maximal obtainable effect and that there were marked differences in the dose-response relationship for different clinical outcome measures. In particular, the dose of FP required to reduce exacerbations was similar to that required to reduce symptoms and improve lung function. Figure 3 Dose-response curve of fluticasone and budesonide in adult asthma for the major clinical outcomes....

Early Intervention

The concept of early intervention with ICS arose with the realization that airways inflammation may be present in patients with clinically mild asthma (100), and that such patients may develop an irreversible component to their airflow obstruction early in the course of the disease (101,102). This led to the question of whether the early introduction of ICS could improve the long-term prognosis, and in particular prevent progressive deterioration of lung function. The key evidence comes from a long-term study comparing initial treatment with ICS or inhaled b2-agonist in patients with newly diagnosed mild asthma (14,16). After two years subjects crossed over treatments and were followed for a further year. Patients transferred to ICS therapy (bude-sonide 1200 mg day) did not obtain the same degree of improvement in lung function, BHR, or symptoms as those who were treated with ICS at the beginning of the study (Fig. 6). An alternative approach has been to examine the association...

AddOn Therapy with a Long Acting pAgonist

It is recommended that if a patient with asthma is inadequately controlled on ICS therapy, a LABA should be prescribed as add-on therapy (Fig. 7) (88,104). However, uncertainty exists as to the optimal ICS dose at which a LABA is needed. This uncertainty is reflected by the British Management Guidelines in which it is recommended that a LABA is added in poorly controlled patients with moderately severe asthma receiving between 200 and 800 mg day of BDP or equivalent (88). This recommendation is based on clinical trials that have shown a dose-response relationship for ICS within this therapeutic range (34-42), and efficacy with adding a LABA to ICS within (and beyond) this range (105-110). increasing inhaled steroid up to 2000 ng doy* addition of a fourth drug e.g, leukotriene receptor antagonist, 5R theophylline, agonist tablet

Alternative AddOn Therapy

Low-dose theophylline represents one option resulting in additional efficacy when used as add-on therapy with low to high doses of ICS (119-121). When used in this way it is likely to result in both bronchodilator and anti-inflammatory effects. However, a recent systematic review suggests that the efficacy of this approach is relatively less than the addition of a LABA, while being associated with greater side effects (122).

Oral Steroid Reduction

The original study of the efficacy of BDP demonstrated its ability to achieve a reduction of oral steroids in patients with severe steroid-dependent asthma (47). Since then ICS therapy across a wide dose range has been shown to be effective in reducing the dose of oral steroids in patients requiring continuous oral steroid treatment (44-46,140-142). While clinicians have predominantly focused on this ability of such high doses of ICS to allow oral steroid reduction or withdrawal, these results also suggest that ICS may have greater effectiveness in the control of asthma than oral prednisone in patients with chronic severe disease. This interpretation is consistent with the greater efficacy of very high doses of ICS (FP 2000 mg day) in improving BHR to both methacholine and AMP than oral steroids (30 mg day prednisolone) (143).

Historical Perspectives

Leukotrienes are so named because they were initially isolated from leukocytes and because their carbon backbone contained three double bonds in series, constituting a triene. However, these molecules were recognized as distinct biological entities several decades before they were chemically defined and purified in the late 1970s. Their role in asthma pathogenesis was first implicated in 1938 after Feldberg and Kellaway noted that cobra venom caused a slow-onset, sustained contraction of smooth muscle in Guinea pig lung perfusate (1). Two years later, they became known as the slow-reacting substances of anaphylaxis (SRS-A), when Kellaway and Trethewie revealed that the time course of this contraction was distinct from that caused by histamine (2). A role in asthma was further suggested in the 1960s when SRS-A was found to be released from lung fragments of a subject with asthma who was exposed to allergen (3) and in the 1970s, when Drazen and Austen demonstrated the effect of...

Future Directions Pharmacogenetics and Novel Therapies

For any given disease, including asthma, there is variability of a given individual's response to a given pharmacotherapy (interindividual variability) and there is variability of a given individual's response to a given therapy on repeated occasions (intraindividual repeatability). Pharmacogenetics is the term applied to the study of the contribution of genetic differences among individuals to the variability in the responses to pharmacotherapy among individuals (186-188). As the response to leukotriene modifiers is not uniform across all asthmatics, and not every asthmatic responds to these medications to the same degree (189), it is hypothesized that an important determinant of responsiveness to these therapies is genetic. Several of the genes involved in the regulation of leukotriene synthesis and degradation have been studied and assessed for functional polymorphic variants that could account for differences in therapeutic responses to these agents. Polymorphisms of the 5-LO...

Molecular Mechanisms

Although several molecular mechanisms have been proposed to explain the actions of theophylline, nonspecific inhibition of phosphodiesterase (PDE) isozymes and non-selective antagonism of specific cell-surface receptors for adenosine are the only ones known to occur at clinically relevant drug concentrations. Theophylline increases the intracellular concentration of cyclic nucleotides in airway smooth muscle and inflammatory cells by inhibiting PDE-mediated hydrolysis. Several distinct isoenzyme families have now been distinguished, based on substrate specificity and the development of selective inhibitors (46). Theophylline is a nonspecific PDE inhibitor that inhibits activation of inflammatory cell types, including T lymphocytes, eosinophils, mast cells, and macrophages, in vitro (47). Inhibition of PDE types 3 and 4 have been reported to relax smooth muscles in pulmonary arteries and in airways (48), while anti-inflammatory and immunomodulatory actions appear to result largely from...

Drug Distribution in the Lung

The total delivered dosage and distribution of chromones in the lung are important factors in determining efficacy in the treatment of asthma. The inhalation airflow rate as well as the method of inhalation will determine the amount of drug reaching the lung (7). Cromolyn is available as an MDI (1 mg and 5 mg), Spinhaler and nebulizer solution (20 mg 2mL). An inhalation rate of 30L min delivers a dose of 5.5 and 11.8 with the 5 mg and 1 mg MDI, respectively, to the lung (11,12). This proportion increases to 16.1 with the addition of a 10 cm spacer using the 1 mg MDI. Therefore, using a large volume spacer will increase the amount of drug delivered to the lung. Laube et al. (13) reported an increase of 8.6 to 11.8 (a nearly 40 increase) of drug delivery to the lung when the inhalation rate was reduced from 70L min to 30L min. This increased drug deposition in the lung resulted in protection against allergen challenge. The use of a spinhaler at lower rates of inspiratory airflow reduces...

Immunoregulatory Effects

Cromolyn and nedocromil have a wide spectrum of activity that includes inhibition of mediator release from mast cells, eosinophils, and neutrophils protection against allergen-induced and exercise-induced bronchospasm and prevention of the early- and late-phase asthmatic response (3).

Allergen Challenge Clinical Trials

Both cromolyn and nedocromil have been shown to have a protective effect in exercise-induced bronchospasm in both children and adults (75,76). Also, these medications have an equal protective effect in response to cold air and bradykinin, substance P, neurokinin A, adenosine, and hypertonic saline (61,77-82). However, nedocromil has been shown to be more effective against sulfur dioxide and sodium metabisulfate (60). On the other hand, Altounyan showed that 10 times the dose of cromolyn is needed to provide 50 protection against sulfur dioxide challenge as compared to the dose needed for allergen challenge (83). An important clinical observation, potentially useful to allergic asthma subjects acutely exposed to allergen, was demonstrated when three doses of nedocromil given acutely over 90 minutes prior to antigen challenge resulted in the inhibition of the late asthmatic response (84). Furthermore, neither cromolyn nor nedocromil prevent the bronchoconstrictor response to inhaled...

Antiinflammatory Actions of Omalizumab

Other inflammatory mediators are also reduced in patients with asthma receiving omalizumab treatment. In a multicenter, randomized, placebo-controlled study of 35 patients with moderate to severe asthma, circulating levels of IL-13 decreased after 16 weeks of omalizumab treatment compared to the placebo group (-2.4pg mL p < 0.01), and non significant reductions were seen in IL-5 (-2.65pg mL) and IL-8 (-1.64pg mL) (97). No differences were detected for IL-6, IL-10, or s-ICAM throughout the study. As IL-13 and IL-5 are produced by Th2 cells, eosinophils, mast cells, and basophils, while IL-6 and IL-10 are produced by Th1 Th2 cells, macrophages and endothelial cells, these results reflect the proposed mechanisms of action of omalizumab. The authors also found that, after 16 and 52 weeks of omalizumab treatment, blood eosinophils were decreased compared with placebo (-25 and -50 , respectively, both p < 0.01). Eosinophilia is one established feature of inflammation (29,30), and...

Tolerability of Omalizumab

Since the first clinical trials in 1999, a total of 4127 patients have received omalizumab in completed studies, of whom 3224 received omalizumab in controlled studies, and 2845 received omalizumab in phase IIB III clinical studies. The majority of adverse events with omalizumab were of short duration and mild-to-moderate intensity. In the phase IIB III studies, adverse events with omalizumab were similar to those in control patients, regardless of asthma severity (Table 2). These 2845 patients each received at least 12 weeks of omalizumab treatment, while 2060 received more than 24 weeks, 688 more than 36 weeks, and 555 more than 52 weeks. In all controlled studies, three patients experienced anaphylactic reactions associated with subcutaneous treatment. One case was attributed to antibiotic use, and the other two resolved with therapy following discontinuation of omalizu-mab. No evidence of immune complex syndrome has been observed in any controlled study. Only one case of a patient...

Clinical Studies

Although azathioprine has been proposed as a treatment for asthma for decades (87) and has been studied in a number of trials, only two small randomized, placebo-controlled studies that recruited a total of 23 subjects have been published (22). These studies were limited by several factors, including the possible presence of comorbid lung disease, inadequate washout (in one study), and no data reporting about oral-steroid consumption (23). No significant differences were observed in the studies for FEVi, FVC, PaO2, and symptoms. One study reported a statistically significant difference in sGaw (specific airway conductance).

Strategies for Allergen Avoidance

At face value, allergen avoidance should be an attractive strategy for managing asthma in patients for whom allergic triggers predominate. This approach is predicated on the relevance ofparticular allergens to the continuing symptoms of asthma, and requires that there should be a simple method to eliminate the relevant allergens or to reduce them to a level at which symptoms will improve. In other words, if there is a threshold level of allergen exposure that you need to get below to achieve benefit, this must be achievable by affordable and practical means. While it is true that extreme forms of avoidance have achieved significant clinical benefits (24), the approaches used in conventional clinical practice have led to only modest reductions in nonspecific bronchial responsiveness (25) and the overall degree of clinical improvement has been disappointing (26). In the context of occupational asthma, where complete allergen avoidance is definitely achievable, it is clear that some...

Emergency Department Assessment

Paramount in the evaluation of AA is determination of attack severity and the risk of respiratory failure. Patients with AA at presentation to the ED or clinic are often in considerable visible distress. Dyspnea and wheezing are common elements in an asthma exacerbation. Among the myriad of other Figure 1 U.S. national statistics on asthma prevalence and mortality show that consistent increases in both these values over the last three decades may have finally reached plateaus. Source Adapted from Ref. 9. Figure 1 U.S. national statistics on asthma prevalence and mortality show that consistent increases in both these values over the last three decades may have finally reached plateaus. Source Adapted from Ref. 9.

Physical Examination

The general appearance of an asthmatic can reveal valuable information to the clinician. Altered mental status, the use of accessory muscles, and interrupted speech patterns have all been implicated with AA (16). In addition, inability to remain supine or diaphoresis has been shown to predict significant airflow limitation, and the combination of these findings portends lower values on objective airflow measurements (17). Derangements in vital signs frequently accompany severe asthma exacerbations. While tachycardia and tachypnea are more frequent, a more discerning gauge of asthma severity may be the presence of an elevated pulsus paradoxus (PP) (16). An abnormal PP occurs when the measured difference in systolic pressure during the respiratory cycle is greater than 10mmHg. Usually the PP is even higher with ranges of greater than 25mmHg, which is highly predictive of poor airflow (18). Caution must be exercised in judging the PP, however, since PP will fall in the exhausted patient...

Alternative Diagnoses

While in most cases of AA, a combination of signs, symptoms, and ancillary measures correlate with a predictable clinical course, several alternative diagnoses should be entertained in the treatment of asthma in most patients, and pursued more aggressively if the setting is correct and the diagnosis of asthma is not entirely tenable. The most commonly missed diagnoses include diseases that cause airflow obstruction themselves or produce acute dyspnea that may be accompanied by wheezing, and include emphysema, chronic bronchitis, bronchiectasis, congestive heart failure, foreign body obstruction, and endobronchial lesions (31). Often, appropriate history, examination, and testing can help distinguish these processes from asthma, but sometimes patients may suffer from one or more of these diseases in addition to asthma. The presence and activity of certain chronic conditions such as rhinitis, sinusitis, and nasal polyposis can affect the incidence of asthma exacerbations (32). The last...

Leukotriene Antagonists

These agents, which are routinely used for the management of chronic asthma, may have a role in the acute setting as well. While having established benefits for mild asthma, use of these agents in the oral form has recently been linked to ED and hospital visits and greater asthma severity (1,119,120). Dockhorn et al. (121), have described interesting advantages of intravenous montelukast over its oral form. In their double-blind, singledose comparison of mild to moderate asthmatics, IV montelukast had earlier PF improvement (as early as 15 minutes) and greater efficacy over oral montelukast. Both the early onset of action and higher efficacy suggested to the authors that IV montelukast may benefit AA patients. To date, only one published report has demonstrated the benefit of IV montelukast in the setting of AA. Camargo et al. (122) showed that 7 mg of IV montelukast was beneficial over placebo in reducing subsequent p2-ago-nist administration, corticosteroid use, improving PF and...

Ventilator Management

The overall goals of MV are to provide adequate ventilatory support and reduce work of breathing to the tired asthmatic until time and ongoing phar-macotherapy corrects the airway obstruction. In cases of severe asthma, strategies aimed at minimizing hyperinflation have been shown to be beneficial. To this end, lowering minute volume ( Ve), decreasing inspiratory time (Ti), and assuring patient-ventilator synchrony become the targets of therapy (161). When ventilation is completely controlled, the addition of ventilator circuit PEEP may worsen hyperinflation (168). In tenuous cases of SAA, sedation should be used to ablate patient-triggered breaths and ventilator PEEP should be set to zero (27). It has been argued that potentially beneficial effects of ventilator administered PEEP are seen as a result of dilating previously collapsed airways, hence allowing improved gas exchange (169) we have not seen this theoretical effect benefit patients and do not employ machine PEEP during the...

Potential Adjunctive Therapies

A number of pharmacologic agents and procedures have been reported to have potential benefit among asthmatics in the ICU. The most noteworthy, unproven therapy is heliox, which has already been discussed above. The infrequent incidence of intubated asthmatics and variation in the expedient availability of helium-oxygen have made it difficult to establish evidence-based efficacy of heliox in mechanically ventilated patients. A number of anecdotal reports by experts argue for a potential role for this The common inhalational anesthetics (enflurane, isoflurane, and halothane) have all been reported to have beneficial effects via smooth muscle relaxation (196-199). Limitations on the use of these agents include lack of proper expertise among medical intensivists concerning anesthetic use and the concomitant restrictions in the applicability of anesthesia ventilators with asthmatics (200). These ventilators have flow and pressure limits that can lead to inadequate tidal volumes and longer...

Justification for Recommendation of Specific Agents

Both the GINA document of 2002 and the NHLBI-NAEPP report of 1997 present evidence-based rationale for selection of specific agents in both children and adults. Long-term controller medications as defined by GINA include inhaled corticosteroids, LABA, systemic corticosteroids, long-acting oral p-agonists, sustained-release theophylline, cromolyn sodium, nedocromil, leukotriene-blocking agents, and steroid-sparing agents. These are widely recognized as the most effective controller medications and the most effective anti-inflammatory agents. There is excellent evidence (Level A) that these reduce asthma symptoms, improve lung function, reduce airway hyperresponsiveness, decrease frequency of exacerbations, and improve quality of live (2,5). Thus, these are preferred treatments for all levels of persistent asthma. The GINA guidelines point out that the relative potencies of the various agents are difficult to elucidate due primarily to relatively flat dose-response relationships. In...

Cromone Mechanism of Action

The exact mechanism of action of cromolyn and nedocromil has not been determined. Multiple mechanisms involving ion channel blockade, blockade of signaling of heat shock protein or G-protein, or even blockade of capsaicin receptor have been identified. However, the final common mechanism appears to be an inhibition of mast cell activation. Studies have reported that the phosphorylation of a 78-kDa-molecular-weight protein prevents mediator release in mast cells (17). More specifically in rat peritoneal mast cells, both medications are reported to phosphorylate a 78-kDa protein from the p and g subunits of the IgE binding protein (FCeRI), which may impair a cell volume-dependent chloride current (17,18). Wang et al. (19) reported that protein kinase C inhibitors prevented phosphorylation of the 78-kDa protein by cromolyn and that this protein was insensitive to protein kinase C activators and Ca2+. This suggests that regulation of an atypical protein kinase C may be involved as an...

Neurogenic Mechanisms of Chromones

The bronchoconstriction induced by sulfur dioxide and bradykinin is inhibited by both cromolyn and nedocromil (Table 2) (60). Inhaled sodium metabisulfate generates sulfur dioxide in the airways with both of these agents causing bronchoconstriction in asthma subjects. The mechanism of action of sulfur dioxide may be through stimulation of laryngeal afferent nerve fibers in experimental animals (61). Nedocromil has been shown to prevent the bronchial hyper-responsiveness in dogs exposed to sulfur dioxide (62). Bradykinin may have broader effects than sulfur dioxide by causing vascular vasodilatation and increased vascular permeability in addition to the bronchoconstrictor effect. The cough and dyspnea induced by bradykinin is blocked by cromolyn and nedocromil (63). In experimental animals, bradykinin has been reported to stimulate afferent C-fibers to release substance P (a mast cell histamine releaser), neurokinin A, and calcitonin gene-related peptide, which all have...

Clinical Use of SABA

Albuterol was the first b2-specific bronchodilator to be used for the treatment of asthma. There was initial evidence that regular treatment with this drug over one week improved symptoms and lung function (38). This encouraged clinicians to prescribe albuterol as a regular long-term treatment in order to maximize bronchodilation, and when fenoterol and terbu-taline were introduced they were also used in this manner. Fenoterol became widely used in certain countries such as New Zealand. However, it was apparent in the 1970s that its use was associated with an increase in asthma mortality. It is now known that regular treatment with fenoterol increases AHR and so increases exacerbation rates (39). It is now generally accepted that the increase in asthma deaths in New Zealand were due to the inappropriate use of regular SABA, leading to increased AHR, coupled with the under-prescribing of anti-inflammatory medications such as corticosteroids (40). The combination of these factors meant...

Leukotriene Biosynthesis

Leukotrienes are fatty acids and members of a larger group of biomolecules known as eicosanoids, which also encompasses cyclooxygenase products such as prostaglandins, thromboxanes, and prostacyclin and the products of 12- or 15-lipoxygenase (the lipoxins) and 5- and 15-lipoxygenase (5,6). Leu-kotrienes are synthesized in mast cells, eosinophils, and alveolar macrophages (7-9), all of which have been implicated as critical effector cells in the pathobiology of asthma. Airway epithelial cells (10,11) and pulmonary vascular endothelial cells (12) may also produce leukotrienes via trans-cellular metabolism (13,14). Leukotriene synthesis is initiated following trauma, infection, inflammation, and a variety of stimuli, including the activation of mast cell antigen-specific IgE bound to Fc receptors (15,16) hyperventilation of cold, dry air (17) aspirin ingestion by aspirin-intolerant individuals (18-20) hypoxia (21) hyperoxia (22) and exposure to platelet-activating factor (23). In these...

Historical Background

Khellin Structure

Cromolyn and nedocromil are members of the chromone group of chemical compounds. The chemical formula for chromone is 5 6 benz-1 4 pyrone (2) (Fig. 1). In 1968, disodium cromoglycate (DSCG) or CS combined with isoproterenol was introduced in the United Kingdom as the first antiinflammatory medication used in asthma (3-5). The addition of the bronchodilator was done to prevent bronchoconstriction that can occur with inhalation of a sodium salt (4). By 1973, cromolyn was approved by the Food and Drug Administration (FDA) for the treatment of asthma and in 1983 for the treatment of allergic rhinitis (5). Khellin (2) was the first identified chromone, which was extracted from seeds of the plant Amni visnaga, the same plant from which cromolyn was derived. It was used as a diuretic and smooth muscle relaxant, especially for the relief of ureteric colic. In 1947, Anrep et al. (6) reported the clinical utility of khellin for the treatment of asthma. Multiple compounds were synthesized using...

Leukotriene Modifiers Safety Considerations

Standard asthma treatments may be complicated by several adverse effects. For instance, p-agonists may cause tachycardia, palpitations, and headaches. Theophylline has a very narrow toxic-therapeutic window, interacts with many medications, and may cause tremors, nausea, and several other ill effects. While systemic corticosteroids have a myriad of adverse effects, including hyperglycemia, growth retardation, hypertension, insomnia, and edema, even inhaled corticosteroids pose risks, including cataracts, thrush, adrenal suppression, and bone loss (162,163). In contrast, the leu-kotriene modifiers continue to have an excellent safety profile and offer the There have been single-case reports of drug-induced lupus (166) and of tubulointerstitial nephritis (167) with some of these drugs, but of most concern is the potential association with the Churg-Strauss syndrome (CSS). Within six months after the release of zafirlukast, eight patients who received the drug for moderate to severe...

Spacers Inhaler Devices

A proportion of patients fail to coordinate actuation with inhalation when using a standard metered dose inhaler (MDI) and greater deposition in the airways can be achieved through the use of a spacer device (139). For this reason spacers are recommended for most asthmatics receiving corticosteroid therapy delivered by MDI, and certainly those on high doses. Technique is still important with spacers. For example, multiple actuations

Dealing With Asthma Naturally

Dealing With Asthma Naturally

Do You Suffer From ASTHMA Chronic asthma is a paralyzing, suffocating and socially isolating condition that can cause anxiety that can trigger even more attacks. Before you know it you are caught in a vicious cycle Put an end to the dependence on inhalers, buying expensive prescription drugs and avoidance of allergenic situations and animals. Get control of your life again and Deal With Asthma Naturally

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