science/technology Asthma Management Project, which had organized and convened under the auspic es of the National Heart, Lung & Blood In stitute of the National Institutes of Health, recommended sweeping changes in treat ment [/. Am. Med. Assoc, 267, 2153 (1992)]. During an asthma attack, the tissue of the airway inner wall is inflamed and the mucus is thick and sticky. Continu ing production of mediators and mes senger substances of inflammation such as histamine and leukotrienes keeps the process going. Recognition of the sj inflammatory component of asth| ma has led to more use of gluS cocorticoid steroids as anti-inflam2 matory agents. And medicinal I chemists are perfecting even newϋ er drugs against mediators of in flammation like leukotrienes, thromboxanes, and phosphodies terases ΙΠ and IV. In seeking the cause of asthma and its increasing frequency, there are plenty of usual suspects to round up. These include heredity, infection, allergy, indoor and out door pollution, and social, eco nomic, and psychological factors. Some of these suggested causes impinge enough on sensitive is sues to make asthma a political and social issue. One key allergic factor in asth ma is atopy. Atopy is response to an antigen with an allergic re sponse of reddening, swelling from influx of water and immune An art competition called "Inspiration in Asthma" cells into tissue, local blood-vessel drew graphic depletions, such as this one dilation, and smooth-muscle spasm. by an English asthmatic, of the sensations of the This type of response is mediated disease. The competition, supported by Zeneca by secretion of immunoglobulin Ε Pharmaceuticals, garnered 600 entries from (IgE) from Β lymphocytes rather asthma patients in 13 countries. A selection of than the less inflammatory IgA 30 of the top entries is now part of a traveling exhibit circulating among asthma associations and IgG. worldwide in hope that doctors everywhere Asthma, therefore, has been will see these patients' expressions of the classified either as allergic or nonasthma experience. allergic. Allergic atopic asthma has been called extrinsic, because the Because of the episodic constriction cause of an episode comes from outside of the bronchial tubes, treatment has the system. Nonallergic nonatopic asthma been based partly on bronchodilation by has been called intrinsic, because it just β-adrenergic agonist drugs. Physicians "happens." The relative incidence of atop did not begin to realize until about 1990 ic and nonatopic has been uncertain. that asthma is really a chronic inflamma In measuring IgE-type responses by tory disease. It was during the 1980s that skin tests, some investigators have found fiber-optics-based instruments became incidences of atopy in as few as 20% of available to examine and sample the air asthmatics, though other groups have ways so physicians could see and test ev found varying higher amounts. Specifical idence of inflammation. As a result of this ly, Jonathan Corne and coworkers in the recognition of asthma as a chronic in Immunopharmacology Group at the Uni flammatory disease, the International versity of Southampton, England, found
ASTHMA ATTACK: FRESH STRATEGIES
Realization that asthma is a chronic inflammatory disease has led to changes in recommendedtreatment Stephen C. Stinson C&EN Northeast News Bureau
D
rowning on dry land. Strangled by your own body. Crushed between massive rocks. These are images people with asthma use to depict what it feels like to suffer from the lung disease in which each breath is a struggle. About 14 million to 15 million Ameri cans suffer from asthma, according to the Centers for Disease Control & Pre vention (CDC), Adanta, including 4.8 mil lion under age 18. And the frequency of the frightening, sometimes deadly disease is getting worse: The prevalence of asthma in the U.S. population increased 46% be tween 1982 and 1993. The death rate has advanced even faster. During the same period, the an nual U.S. death rate from asthma for people 24 years old and younger more than doubled to 3 7 deaths per million population from 1.7 per million. Similar trends are reported from countries in Europe and Asia. Asthma is a costly dis ease as well, with emergency room vis its and hospital admittances also on the rise. Epidemiologists naturally wonder if changes in reporting or changes in diag nosis are the source of the rising num bers for incidence, severity, death rates, emergency room visits, and hospital ad mittances. "Increased" numbers of asth ma cases may be an artifact of improved medicine. But even when examined for these sources of distortions, the worsen ing statistics related to asthma are very real by every means measured. Asthma is an obstructive lung disor der. The obstructive episodes, in which patients have difficulty taking in enough air, are reversible either spontaneously or on treatment with drugs. Asthma can be made worse or precipitated into acute attacks by allergens, irritants, flu, cold air, vigorous physical activity, or emo tional upset.
JANUARY 6, 1997 C&EN 25
science/technology Leukotrienes mediate airway inflammation
Arachidonic acid
Leukotriene B4 (LTB4)
5-HPETE
Leukotriene A4 (LTA4)
Leukotriene D4 (LTD4) Leukotriene C 4 (LTC4) 5-HPETE = 5-hydroperoxy-6-frans-8,11,14c/s-eicosatetraenoic acid Cys = cysteine Gly = glycine Glu = γ-glutamate
Leukotriene E4 (LTE4)
atopy in 90% of 198 asthmatics they stud ied [Lancet, 344, 344 (1994)]. In explain ing their findings, Corne and coworkers note that evidence of atopy shows up better at some ages than others. The true incidence may be 100%, and all asthma may be of the allergic type, some re searchers suspect. The original cause of asthma, then, may be the immune system "learning" to respond to antigens with IgE rather than IgA or IgG. There seems to be a time in earliest childhood when the immune sys tem learns preferentially to mount IgE re sponses to antigens in particular organs and tissues, with the result that the per son develops allergic dermatitis, hay fe ver, or asthma. The resulting asthmatic atopy seems to be tissue-specific. Physicians Paul A. Corns and John H. Dark at Freeman Hos pital, Newcastle upon Tyne, England, re port that two asthmatic patients who got lung transplants from nonasthmatic do nors did not redevelop asthma. And two patients with severe cysticfibrosiswho got lung transplants from mildly asthmat ic persons went on to develop asthma themselves [Lancet, 341, 1369 (1993)]. Corris and Dark write, "These observa26 JANUARY 6, 1997 C&EN
tions support the notion that asthma is a local' disease." Whatever causes people to become asthmatic, studies in identical twins in dicate about a one-third contribution from heredity. Among recent findings, physician Dirkje S. Postma of University Hospital, Groningen, the Netherlands, and coworkers studied genes of 303 chil dren and grandchildren of 84 asthmatics [N. Engl. J. Med, 333, 894 (1995)]. They found links between a region on chro mosome 5 and both hyperreactivity of airway tissue and raised serum levels of IgE. And physiology professor Stephen B. Harrap of Australia's University of Mel bourne found a linkage between a gene for the high-affinity receptor of IgE on a region of chromosome 11 and bronchial hyperreactivity in a study of 123 pairs of brothers and sisters [Lancet, 346, 1262 (1995)]. But heredity and genetic predisposi tion may not be the whole story. For example, children of native peoples who have migrated from outlying areas of South Africa and South Pacific islands to Capetown and New Zealand have higher incidences of asthma than those who stayed behind. In the U.S., there
are pockets of high asthma death rates in New York City and in Chicago. In 1993, the most recent year for which data are available, CDC found that blacks aged 15 to 24 were six times as likely to die of asthma as whites in the same age group. And blacks between birth and 24 years old were 3.4 times more likely than whites to be hospitalized for asth ma [/. Am. Med. Assoc, 275, 1535 (1996)]. In searching for causes of asthma in ur ban environments, doctors suggest that closer living quarters in cities means more exposure to such antigens as house dust mites, cat dander, cockroaches, and sec ondhand tobacco smoke. Feces of the ev er-present house dust mite Dermatophagoides pteronyssinus contain particles of dried protease digestive enzymes. Cat dan der contains dried saliva, which also has protease activity. It may be that inhalation of such enzyme-active dusts leads to breaches of the inner linings of the airway, and thus to invasion of airway tissue and the first raisings of IgE responses. Outdoor air pollution is another obvi ous suspect. Yet the current increase in all measures of asthma incidence and se verity began in the late 1970s, after years of slow decline. And the decades of the
Thromboxanes mediate bronchoconstriction
Arachidonic acid
Prostaglandin G 2 (PGG 2 )
Prostaglandin H 2 (PGH2)
Thromboxane A 2 (TXA2)
1970s, '80s, and '90s have been a period of gradual improvement in air quality. Physician David M. Lang and biometrician Marcia Polansky of Hahnemann Uni versity Hospital, Philadelphia, studied death rates from asthma in that city ver sus reported atmospheric levels of carbon monoxide, nitrogen dioxide, sul fur dioxide, ozone, and particulates [N. Engl. J. Med, 331, 1542 (1994)]. They found that the death rate from asthma rose to 2.41 per 100,000 population in 1991 from 0.68 per 100,000 in 1977. Yet the incidence of unhealthful days—days when concentrations of pollutants ex ceeded the Environmental Protection Agency standards—decreased during that period. On dividing their population among 365 census tracts in Philadelphia, the Hahnemann investigators found a dis proportionate number of deaths in mi nority neighborhoods, especially among blacks. Sometimes asthma is provoked by cold air and exercise. Physician E. R. McFadden Jr., of Case Western Reserve University School of Medicine, Cleve land, has suggested a mechanism [N. Engl. J. Med, 330, 1362 (1994)]. Cold air itself, or rapid, deeper breathing dur ing activity, cools all the airways, even the deepest. In response, increased amounts of blood move into the capil laries surrounding the airways to rewarm the airway tissue. Large amounts of blood in the abnormally plastic capil lary beds of asthmatics causes collection of fluid in tissues, thus constricting the airways. Though little is known for certain about why people become asthmatic, drugs can keep asthma under control and reverse asthmatic episodes. Asthmat ic symptoms may be partly an imbalance between the bronchoconstrictive action of the cholinergic nervous system and the bronchodilatory effect of the β-adrenergic system. One anticholinergic agent is ipratropi um bromide, a derivative of atropine that lacks many of atropine's unpleasant side effects. The patient inhales an aqueous solution of the drug by mouth out of an aerosol can or spray pump. Drugs that act on the β-adrenergic system target β-receptors. The β-receptors in lung tissue are of the β2 type, different from β,-receptors in heart tis sue. Medicinal chemists have progressed over the years to the discovery of β2selective agonists. The action of β-agonists stimulates adenylate cyclase, which converts adenosine triphosphate to cyclic
'
senger compounds that me diate inflammation. One newer drug blocks And in December, the leukotriene receptors . . . agency approved zileuton for marketing by Abbott Laboratories, North Chica go. Zileuton inhibits 5-lipoxygenase, which cata lyzes conversion of arachidonic acid to 5-hydroperoxy6-trans-8,11, l4-c&-eicosatetZafirlukast raenoic acid, a step on the metabolic pathway to the synthesis of leukotrienes. . . . another blocks Two drugs in a class by leukotriene syntheses . . . themselves are cromolyn and nedocromil. These in halants have chromone (ben^y zopyranone) units in their structures. Neither drug has bronchodilating activity, and Zileuton patients use them for pro phylaxis to prevent attacks. . . . and another blocks Cromolyn is thought to act thromboxane receptors by stabilizing mast cells and preventing mast cells from secreting from their inter nal granules such media tors of inflammation as his tamine and leukotrienes when allergens bind to IgE molecules on mast cell surfaces. More recent evidence Seratrodast suggests that whatever cro molyn may do to mast cells, adenosine monophosphate (cAMP), a sec it blocks the effects of certain peptide neu ond messenger substance that mediates rotransmitters in airway nerves that trigger bronchoconstriction. Nedocromil inhibits bronchodilation. Several ^2'2L(^rtner^c drugs are ap release of inflammatory messenger sub proved in the U.S.: albuterol, bitolterol, stances from more types of inflammatory pirbuterol, salmeterol, and terbutaline. cells than just mast cells. Nedocromil may These are inhaled as powders or aero also have inhibitory effects on peptide sols of solution, or taken internally as neurotransmitters. One unique drug is theophylline. This tablets or syrups. In addition, the older, nonspecific β-agonist epinephrine is bronchodilator is thought to act by inhi available as an inhalant over the counter, bition of phosphodiesterase IV, an en while the likewise nonspecific ephed- zyme that catalyzes breakdown of cAMP. rine is in over-the-counter tablets and Receipt of a signal for bronchodilation causes formation of the second messen syrups. Corticosteroids used as anti-inflamma ger cAMP from adenylic acid by adenyl tory agents include beclomethasone ate cyclase. Preventing cAMP hydrolysis dipropionate, budesonide, flunisolide, prolongs duration of the signal, leading fluticasone propionate, prednisolone, to prolonged bronchodilation. But the therapeutic dose for theophyl prednisone, and triamcinolone acetonide. These are formulated as inhalers, line is very close to the toxic dose. Side effects are diarrhea, headache, insomnia, tablets, or syrups. Just last September, the Food & Drug and nausea and vomiting. And an over Administration cleared zafirlukast for mar dose can lead to seizures, brain damage, keting by Zeneca Pharmaceuticals, Wil and death. For these reasons, some doc mington, Del., as an oral drug to treat asth tors tend to shy away from theophylline ma. The drug acts by blocking cell surface as newer P2-adrenergic agents and ste receptors for leukotrienes, which are mes- roids appear. JANUARY 6, 1997 C&EN 27
science/technology of these agents in manag The chief value of theo ing asthma. Salmeterol and phylline today seems to be Short-acting β-agonists formoterol last about 12 prophylactic, to prevent hours as opposed to four episodes during the night, to five hours for the short or in persons about to en er-acting types of albuterol, gage in vigorous physical bitolterol, pirbuterol, or activity. In addition, some terbutaline. physicians favor theophyl But the longer-acting line to supplement P2-adrenAlbuterol Bitolterol types also need more time ergic agents and steroids in to take effect. Thus, many order to use those other doctors urge that asthmatics drugs in lower doses. And not use longer-acting β 2 ^οthere is renewed interest in nists to treat an acute attack. theophylline because of in Rather, longer-acting drugs dications that it modifies can be used to get a patient the immune response, re Pirbuterol Terbutaline through a night or through lieves inflammation, and a bout of planned physical protects airways from anti activity. gens in ways that seem to . . . now joined by longer-acting ones go beyond any activity as a The Asthma Manage phosphodiesterase inhibi ment Project recommends tor. Theophylline-ephedusing longer-acting agents rine combinations are avail further along in a stepwise able in tablets and syrups course. With intermittent over the counter. asthma, inhaled short-act ing β2^οηΐ8ί8 used only Despite the wealth of Formoterol as needed are drugs of drugs available to treat choice. In mild persistent asthma, several seem as asthma, the best therapy is problematic as theophyl not more of the short-act line in actual use. And al ing β2^οηΐ8ί, but addition though the International of an inhaled steroid, an in Asthma Management Proj Salmeterol haled cromolyn-type drug, ect has adopted a step-bysustained-release theophyl step regimen for drug treat line tablets, or both. Only ment, not all doctors in the U.S. are comfortable with some drug The drug firm Sepracor of Marlbor if asthma is or becomes moderate to se types. ough, Mass., is leading an effort to re vere and persistent should an inhaled Several concerns have surfaced about develop the currently marketed racemic long-acting β 2 ^οηί8ί be added to the inhaled β-adrenergic agents. Observers albuterol as the (R>isomer. Company sci other drugs. have noted periodic spikes in the fre entists point to studies that indicate that But such ideal stepped approaches, quency of asthma deaths on a per capita (i?>alt>uterol is the bronchodilator, where which include inhaled steroids, bother basis in the U.K. and New Zealand—so- as (5>albuterol heightens airway respon some doctors who are worried about ste called asthma mortality epidemics. Each siveness to bronchoconstricting stimuli. roids. Steroids can affect physical growth occurred after treatment with certain In addition, (^albuterol is metabolized and development of hormone-based sys β-agonists began: epinephrine in 1935, more rapidly than the (S>isomer, leading tems in children. And some physicians isoprenaline in 1948, high-dose isopren- to possible accumulation of the "other" worry about rebound asthma on sudden aline in I960, and fenoterol in 1975. isomer. ly stopping steroids for some reason. So Paradoxically, each spike rose and sub Inhaled β2^οηΐ8ΐ5 have even gotten drug management of asthma in the U.S. sided over a 15-year period, though caught in the controversy over use of is likely to be colored by individual prac β-agonists remained in use during these chlorofluorocarbon aerosol propellants. titioners' preferences and patients' re regressions. The agents are usually sprayed with a sponses to therapy. A second concern about β-adrener mix of CFC-11 (trichlorofluoromethane) Amid all the controversy, the one gic agents is whether they dilate air and CFC-12 (dichlorodifluoromethane) thing certain is that asthma is controlla ways so effectively that the patient ac as propellant. In August 1996, FDA ap ble by avoidance of obvious allergens tually breathes in more of the offending proved an aerosol of albuterol propelled and proper use of drugs. The most likely allergen, thus exacerbating the asthma by 1,1,1,2-tetrafluoroethane (HFC-134a) cause of problems is doctors' and pa for marketing by Schering-Plough, Madi tients' failing to work together to make further. A third issue is whether β-adrenergic son, N.J. The metered-dose inhaler will the patient aware that asthma is an ongo agents, which are all chiral and all mar be produced for Schering-Plough by 3M ing process and not just episodes in iso lation. Easy-to-use instruments let pa keted as racemates, should be sold as sin of St. Paul, Minn. gle enantiomers. At question is whether Appearance of such longer-acting in tients test their lung functions at home the "other" isomer is actually a broncho- haled β2^οηί8ί$ as salmeterol and for and be aware of a deterioration that may constricting agent. moterol raises questions about the roles precede an attack.^ 28 JANUARY 6, 1997 C&EN
