ASTHMA: BREAKTHROUGHS IN THERAPY

      The inflammatory component of asthma continues to be the focus of research efforts, and the immunopathogenesis is slowly unfolding to provide some intriguing opportunities for interrupting the inflammatory process. Hyperreactivity is in part mediated by the action of an immune protein, interleukin-4 (IL-4), on aberrant activation of T-helper (Th)-2 effector systems in the airways of asthmatics, which leads to an influx of eosinophyls and CD4+T cells to the lungs and increases in Th2 cytokine production and immunoglobulin-E levels. To produce the airway hyperreactivity that characterizes asthma, IL-4 must be present at the time of allergen exposure, so it seems logical to interrupt the process at that point. To accomplish this, Immunex has produced soluble Interleukin-4 receptor (IL-4R) that binds and neutralizes the activity of IL-4; and the product is currently undergoing Phase-I and Phase-II studies.
     Nonspecific bronchial hyperresponsiveness may also be due to the priming of airway smooth muscle by leukotrienes, so this is also a logical point of attack. In spite of numerous complications in bringing them to market, leukotriene receptor antagonists are the single biggest marketed innovation in asthma therapy in many years. Instead of merely treating symptoms with bronchodilators or broadly suppressing the immune response with corticosteroids, these agents allow interruption of asthma’s pathogenesis much farther up its chain of events with much tighter focus. Leukotrienes, discovered in 1979, ultimately mediate the production and tissue attachment of IgE, the immunoglobulins largely responsible for the allergic response of asthma. With the widespread misuse of metered dose inhalers, the oral dosage forms of this type of agent are considered a significant advantage for many patient populations.
     Merck’s first attempt at a marketable product, Venzair underwent clinical trials in 1991, but was ultimately rejected because of its tendency to cause liver damage, an unacceptable side effect in a medication designed for pediatric or long-term use. Leutrol (Abbot’s zileuton) suffered a similar fate in 1995, but has since been approved (as Zyflo) with cautions to monitor liver function; and Accolate (Zeneca’s zafirlukast) hit the market in November of 1996. Ultair, (SmithKline Beecham’s pranlukast), already on the Japanese market, and Singulair (Merck’s montelukast), a long-acting variation are expected to be approved sometime this year; while tomelukast, pobilukast, and verlukast are lined up in the research pipeline. Leukotriene synthesis inhibitors will be next in line for development.

NEW TRICKS FOR OLD DOGS
      While certainly not new itself, administration of albuterol is undergoing some changes that can be considered breakthroughs on their own. Studies are showing chiral R-albuterol to be more efficacious than the racemic mixtures currently on the market, with lower effective doses and a more favorable side-effect profile. Albuterol is also on the front lines of a movement by pharmaceutical manufacturers to become “green” by replacing the CFC’s in metered dose inhalers with propellants that don’t damage the ozone layer – not so much by choice as necessity, for the international ban on CFC’s will eventually demand discontinuation of current inhalers. Expect the MDI’s you dispense so frequently now to disappear over the next few years to be replaced by better products utilizing green propellants and improved delivery systems.
     In recent years, therapeutic problems deriving from the old standby MDI’s have surfaced to prompt a second look at their design, so the demand for change from CFC’s has spurred an evolutionary leap in metered-dose technology. Inhalers suffer from loss of prime, that is, the first actuation after an inhaler has been standing may deliver significantly less than a proper dose, depending on the product itself, the orientation of the canisters while stored, and the duration of storage between actuations. They also can deliver inaccurate doses when the active ingredient settles out of solution or suspension and when the canister empties. Of course the tendency of inhalers to deliver large portions of their doses to the nasopharynx rather than the lungs when used by the average patient without a spacer device of some kind is well documented. Now the CFC’s have come under scrutiny concerning their effects on essential rubber components of the actuator valves in inhalers, as they tend to extract polycyclic aromatic hydrocarbons, an air pollutant that shares with ozone a large measure of responsibility for exacerbations in asthmatics. It can hardly be efficacious to provide a damaging pollutant along with a dose of medication.
     The metered-dose inhalers, seemingly so simple, are very complex, multi-faceted products. The canister contains not only the active ingredient suspended or dissolved in solution, but a surfactant that acts both to maintain the integrity of the suspension and to lubricate the actuator valve, and the propellant. The new hydrofluoroalkane propellants chosen to replace the CFC’s have required development of new surfactants, for those used with CFC’s are not sufficiently soluble in HFA. The metering valve of actuators, so essential in delivery of consistent and accurate doses, is comprised of seven or eight metal or plastic components manufactured to rigorous tolerances. HFA adversely affects the plastic parts used in these valve mechanisms, so new elastomers had to be developed. New surfactants tended to deliver unsatisfactorily coarse sprays, so the valve mechanisms themselves have had to be redeveloped to counter that problem.
     The first entry to the “green” market is Schering’s Proventil HFAâ. Its new propellant (hydrofluoroalkane), keeps the product fully aerosolizable in cold conditions and in any storage position to avoid underdosing and repriming, its MDI mechanism has been redesigned to spray with less force than other albuterol inhalers and to deliver a significantly more accurate and consistent dose. Other albuterol sprays on the market tend to deposit a large portion of each dose forcefully on the back of the pharynx, contributing to the waste and ineffectiveness of these products in the hands of a great many users. The reduced force of the new MDI promises to enhance the effective utilization of each dose by reducing this waste and increasing the amount actually inhaled without the aid of a spacer device.

INCREASE IN ASTHMA ASSOCIATED WITH INDOOR ALLERGIES
      Mortality from asthma is attributed to a combination of factors, including inadequate assessment of severity by physicians, delayed treatment, lack of patient education, and suboptimal control with medications. Most patients who die from asthma had poor understanding of the disease and their prescribed therapies, unable to assess the danger of a deteriorating condition until critically late.
     Accessibility of quality health care continues to be an issue, as patients of lower socioeconomic status in inner-city areas without health care insurance are less likely to be properly diagnosed and treated and more vulnerable to severe attacks that can become lethal. The asthma-associated death rate for blacks continues to remain higher than for whites, and the death rate for those of Puerto Rican descent is on a sharp rise.
     The NIH issued guidelines for asthma diagnosis and management in 1991, but only 22% of recently surveyed primary care physicians were able to demonstrate effective utilization of those guidelines, many reluctant to prescribe inhaled corticosteroids because of perceived liabilities. The Asthma Zero Mortality Coalition (AZMC), composed of a smorgasbord of concerned lay and professional associations has now taken the lead in preventing deaths from asthma. Foremost among the Coalition’s recommendations is that inhaled steroids combined with beta-adrenergic agonists have become the hallmark of management of moderate to severe asthma and thus prevent a great many hospitalizations. Physicians are urged to prescribe and patients are educated to comply with regimens that rely on regular dosing with such products, an effort at overcoming the associated "steroidophobia".
      In spite of overall improvements in air quality and reduced exposure to tobacco smoke over the past few years, the incidence and severity of asthma has continued to increase at an alarming rate. The trends for adults tend to parallel the periodic increases in ozone during hot weather and seem to make perfect sense. The increases seen in children, though, are not so straightforward, for they are evenly dispersed over geographic areas of disparate pollution levels.
     This pediatric asthma pandemic seems to defy logic, since known contributing factors are being minimized, professional knowledge and patient education are improving, and pharmacotherapy is getting more effective. Every expert seems to have a theory about the paradox. Indoor allergens like roach and dust mite feces, pesticides, lead, cadmium, arsenic, polycyclic aromatic hydrocarbons, mold spores, and volatile organic compounds (like formaldehyde in wood products), are the likely culprits -- all present in indoor air in higher concentrations these days because of efforts to make our homes more energy-efficient. The hypothesis is that early exposure to high concentrations of these antigens predisposes children to develop asthma either by sensitization or genetic imprinting to produce the protein allergic mediators.
     Lower socioeconomic status also seems to be a logical predisposing factor, poorer populations enduring greater exposure to indoor antigens due to lower levels of sanitation. The fall of the Berlin Wall brought new evidence, though; for East German children, with widespread poverty, suboptimal sanitary conditions, and exposure to sulfur-containing industrial pollution rather than western vehicle exhausts, showed substantially lower incidence of asthma. It seems that East German children, far more likely to attend day care centers, were exposed to and contracted far more early viral bronchitis. This lends credence to the theory that early viral exposure somehow redirects the immune system's efforts toward viruses rather than allergens.
     Thus, short of facilitating viral infections, a measure that would obviously raise eyebrows, the logical option for preventing development of asthma in children is avoidance of early exposure to those antigens. Encase mattresses and pillows in mite-proof covers; eliminate rugs, carpets, and fabric curtains; minimize influx of outside dust particles from tracking (by making your home a "no-shoe zone"); keep the cat outside; and keep your home rigorously clean. Exterminate for roaches; use tannic acid mite killers on fabric furniture; use air conditioning when outside allergens are high; and make sure those filters are kept clean. Get rid of stuffed animals, and keep shelving to a minimum. Anything you can do to minimize the collection of dust will help.

PHARMACOTHERAPY
      Asthma remedies have historically been fraught with side effects, for even the most selective of beta-2 agonists in small doses may precipitate some nervousness, tremor and sleeplessness in sensitive patients. Treatment, of course, depends upon the severity and frequency of asthma attacks, with the minor infrequent attack once or twice weekly being effectively treated with an inhaled PRN beta-2 agonist. The patient may benefit dramatically by the addition of routine dosing with nedocromil or cromolyn to his regimen. Though the exact mechanisms of action of these agents remains elusive, and they exert no immediate symptomatic relief whatsoever, they are thought to stabilize the membranes of mast cells and block the release of chemical mediators responsible for both the initial bronchospastic phase of asthma as well as the inflammatory hyperreactive phase.
     The regular use of one of these agents may eliminate the necessity for any further measures in many patients, particularly in those suffering from exercise-induced asthma. In patients whose attacks are more frequent or are severe enough to seek emergency treatment or hospitalization, more aggressive measures are obviously appropriate. Here again, once the acute emergency of a severe attack is overcome, prevention of future attacks and mitigation of their severity are crucial. In order to effect these changes it is imperative that the consequences of the secondary inflammatory phase of the attack be adequately addressed.
     Systemic glucocorticoids are unquestionably effective for this purpose, but their side effects make them a choice of last resort. Any of the various inhaled glucocorticoids can be added to regimens of beta-2 agonists and/or nedocromyl or cromolyn without complication; and properly used, their systemic effects are minimal.
     With all inhaled medications, proper administration remains a primary concern, for if administered improperly, such medications can do more harm than good. Care should be taken to ensure that multiple inhalers are utilized in the proper order and that an adequate amount of time is allowed after a beta-2 agonist and before another product is administered. This will help to maximize penetration and the benefit of the second agent.

Some Sources of Valuable Information

* The National Jewish Center for Immunology and Respiratory Medicine 1400 Jackson St. Denver, CO 80206 800-222-LUNG
"Your Child and Asthma"
"Understanding Immunology"
"Management of Chronic Respiratory Disease"

* The American Academy of Allergy and Immunology 800-822-2762
 "Allergy and Asthma"

* Asthma and Allergy Foundations of America 1125 Fifteenth St., NW, Suite 502 Washington, DC 20005 800-7-ASTHMA

* National Asthma Education Program Information Center 4733 Bethesda Ave., Suite 530 Bethesda, MD 20814 301-951-3260 http://www.nhlbi.nih.gov/nhlbi/nhlbi.htm

* American Lung Association 1740 Broadway New York, NY 212-251-1222 http://www.lungusa.org

* Allergy and Asthma Network/Mothers of Asthmatics, Inc. 3554 Chain Bridge Road, Suite 200 Fairfax, VA 22030 703-385-4403 http://www podi.comlhealth/aanma