new perspectives 3 drug present and

Thorax 1993;48:176-182

British Association for Lung Research review series Series editor: D F Rogers

New perspectives on basic mechanisms in lung disease * 3

Drug intervention in asthma: present and future

V A Alabaster, B A Moore

In Western industrial countries asthma affectsabout 5% of the adult population and10-15% of children. Asthma is now the mostcommon chronic respiratory disorder seen ingeneral practice in Britain, with over 1 mil-lion consultations a year.' Epidemiologicalstudies suggest that its prevalence, severity,and mortality are rising -and, although redefi-nition of diagnostic criteria and a greaterawareness of the disease may contribute tothe increase, there is evidence that environ-mental factors, such as increased exposure toallergens and atmospheric pollutants, may bea contributing factor.Drug treatment in asthma has changed

during recent years, reflecting the increasedawareness that asthma is not just a disease ofreversible bronchoconstriction and that theunderlying inflammation occurring in the air-ways contributes in a major way to the patho-logical processes and progress of the disease.Over the past few years knowledge of thebasic mechanisms underlying the inflam-matory process has greatly increased and aplethora of chemical substances have nowbeen identified that are known to be releasedfrom a wide range of different inflammatorycells. These chemical substances (nowtotalling 25-30) could all potentially have arole in the inflammatory process. Thepredicament for the drug discoverer is thatthe possibilities for drug intervention in theinflammatory process appear endless and areincreasing as new knowledge emerges. Thisarticle aims to cover the current thinking onasthma treatment and to look to the future,both immediate and more long term, fromthe viewpoint of the discovery of drugs in thepharmaceutical industry.

Current asthma treatmentHistological studies of lungs from patientswho died of asthma show profound inflam-matory changes with occlusion of major air-ways with inflammatory cells, epithelial cells,and mucus plugs.2 Biopsy specimens frompatients with asthma who have minimalsymptoms, however, also show characteristicfeatures of inflammation, including sheddingof ciliated epithelium, eosinophil infiltration,partial mast cell degranulation, and collagendeposits beneath the epithelial basementmembrane.3 During the past 10 years therehas been an increased realisation that airway

inflammation is a major pathological featurein asthma and is likely to contribute to thesymptoms and bronchial hyperresponsivenessthat is characteristic of the disease. This hasled to the recommendation that anti-inflam-matory treatment should be started at anearly stage.45 Of the commonly used drugs,inhaled and orally administered cortico-steroids appear to be the most potent anti-inflammatory agents. Although systemicsteroids are of benefit for patients with severeor refractory asthma their side effects limittheir general use. Introduction of the inhaledcorticosteroids (beclomethasone, triamcino-lone, flunisolide, and budesonide) provided amajor advance in the treatment of asthma.When these agents are administered before anallergen challenge to sensitised patients, thelate phase bronchoconstrictor response andincrease in bronchial hyper-responsivenessare inhibited whereas continued administra-tion will also reduce the immediate responseto allergen6 and reduce bronchial hyperre-sponsiveness and symptom scores in patientswith asthma.7 This therapeutic effect of topi-cal steroids is likely to be multifactorial,resulting from the suppression of the actionsof several types of inflammatory cell, includ-ing macrophages, eosinophils, lymphocytes,and mast cells.7 8 Therapeutic benefit can beobtained by inhaling doses below 800 ,ug/day,generally with minimal side effects, in adultsand children.9 Some patients, however,respond only to higher doses, which mayresult in adrenal suppression, growth retarda-tion, osteoporosis, and haematologicalchanges.10 Other local effects, such as dys-phonia and oral candidiasis, may limit thedosage." To improve on the currently avail-able inhaled steroids, drugs with higher topi-cal activity and reduced local and systemiceffects are needed. One such recently intro-duced agent is fluticasone propionate, whichhas negligible oral bioavailability as a conse-quence of limited absorption from the gas-trointestinal tract and virtually complete firstpass metabolism.'2 These properties could behighly advantageous for inhalation in man,where a substantial fraction of an inhaleddose is normally ingested by swallowing.'2

Alternative anti-inflammatory preparationsare available in the form of cromolyn andnedocromil. The mechanism of action ofthese drugs is unknown, but may includestabilisation of inflammatory cells and effects

Pfizer CentralResearch,Ramsgate Road,Sandwich CT13 9NJV A AlabasterB A MooreReprint requests to:B A Moore

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Drug intervention in asthma: present andfuture

on local nerve endings.'3 Cromolyn has noappreciable bronchodilator activity, but givenlong term (for more than 12 weeks) willreduce airway hyperresponsiveness in patientswith asthma, and in shorter term use (forunder six weeks) is effective in preventingseasonal increases in bronchial hyperrespon-siveness."3 Cromolyn appears to be a lesseffective anti-inflammatory agent, however,because improvements in bronchial hyperre-sponsiveness may be variable and may not bemaintained;46 moreover, the dosing regimens(2 mg four times a day) may not be conven-ient.6 Although cromolyn has been claimed tobe equieffective in children and adults'3 it isprescribed more usually in children becauseof concerns about the growth retardation pro-duced by steroids. Nedocromil has a clinicalprofile similar to that of cromolyn and mayprovide a sustained decrease in bronchialhyperresponsiveness. Unlike steroids, theygive no appreciable improvement in FEV,with prolonged usage.6

Although an inflammatory basis for asthmais now widely recognised and inhaled pro-phylactic anti-inflammatory agents areincreasingly prescribed, there still remains theneed to achieve acute relief of symptoms bythe use of bronchodilator agents. The inhaled2 adrenergic agonists (salbutamol, terbu-taline, fenoterol) are by far the most effectivebronchodilators in current use.2 These agentshave a rapid onset of action and are indicatedas first line treatment for the short term reliefof bronchoconstriction and acute exacerba-tions of asthma symptoms.2 4 New long actinginhaled , agonists (salmeterol, formoterol)are now becoming available, but in view ofthe debate about continued regular use of 3agonists'4 as opposed to on demand treat-ment the place of these agents in the treat-ment of asthma cannot be certain. The twicedaily dosing regimen and long acting effect,however, will no doubt benefit manypatients,'5 though the clinical relevance ofearlier claims for an anti-inflammatory effectof salmeterol is at present unclear.'5

Anticholinergic bronchodilators, such asipratropium or oxitropium, are also used inasthma, and have utility in certain subsets ofpatients. Subtypes of muscarinic receptorshave now been recognised in the airway;agents selective for the smooth muscle (M,)receptor should prove to be useful and have agreater potential than non-selective agents forincreased effect.2

Novel drugs in early clinical developmentOver the past 20 years research on asthmahas focused on the identification, elucidation,and synthesis of chemical substances releasedfrom mast cells, neutrophils, and eosinophilsduring antigen challenge. This led to thedesign and development of several antagonistdrugs as potential drugs for asthma.Histamine antagonists proved to be disap-pointingly ineffective and research effort thenturned to the three groups of potentiallyimportant mediators derived from activation

of membrane phospholipids by phospholipaseA2, the cyclooxygenase products, lipoxygen-ase products, and platelet activating factor(PAF)-see figure 1. Lung tissue canmetabolise arachidonic acid either via thecyclooxygenase pathway, giving metabolitesthat can be proinflammatory (prostaglandin(PG) F2a, PGD2, PGH2, and thromboxaneA2) or anti-inflammatory (PGE2 and PGI2),or via the 5-lipoxygenase pathway, givingbronchoconstrictor and proinflammatoryleukotrienes. The prostanoids, leukotrienes,and PAF have all been shown to be releasedin appreciable amounts during an allergenchallenge, though the profile of productschanges in the early or late reaction. Non-steroidal anti-inflammatory drugs that inhibitthe enzyme cyclooxygenase and prevent for-mation of the prostanoid precursor PGH2have been evaluated in asthma. Conflictingresults have been produced and, althoughmost studies suggest that indomethacin orflurbiprofen have some small beneficialeffects,'6 a few patients become worse withthis treatment. It has been suggested thatthese compounds cause a shunting of arachi-donic acid metabolism to the lipoxygenasepathway, with a subsequent increase inleukotriene concentrations. More promisingtargets were considered to be interventionfurther down the arachidonic acid cascade-namely, inhibition of thromboxane A2(TXA2), leukotrienes (LT), and PAF.

THROMBOXANE SYNTHETASE INHIBITORSAND ANTAGONISTSThromboxane receptors are widely distrib-uted in airway smooth muscle of variousspecies. In man they mediate constrictorresponses not only to TXA2 but also to otherprostanoids, such as PGD2 and PGF2a Twoclasses of compounds have been developed,compounds that inhibit the synthesis ofTXA2and compounds that block the action ofprostanoids on the thromboxane receptor.The potential of thromboxane synthetaseinhibitors is now considered to be limitedbecause synthesis of endoperoxide stilloccurs, with the consequent transformationto other prostanoids, which activate thethromboxane receptors just as thromboxanedoes. Nevertheless, the thromboxane syn-thetase inhibitor OKY-046 (ozagrel) has beenreported to show some inhibition of bron-choconstriction in allergen challenge stud-ies,'7 and is being developed in Japan for thetreatment of asthma. Conceptually throm-boxane receptor antagonists hold morepromise and two such antagonists have beentested in asthmatic patients, GR32191 andICI92605. The results of early allergen chal-lenge studies were promising becauseGR32 191, for example, produced modestreductions in allergen induced bronchocon-striction.'8 In a subsequent four week study,however, the compound had no effect onmorning and evening peak expiratory flowrates, subjective symptom scores, or noctur-nal dyspnoea.'9

These results suggest that prostanoids act-

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Membrane phospholipid

Phospholipase A2

Lyso-PAF Arachidonic acid

PAF Cyclooxygenase 5-Lipoxygenase

PGG2, H2 l lLTB4 LTC4, D4, E4

PGE2, F2Q 12, D2TXA2

Figurel Formation ofplatelet activating factor (PAF), prostaglandins (PG), andleukotnienes (LT) during the allergic response. TX-thromboxane.

ing via the thromboxane receptor do not havea key role in asthma. Further evidence will,however, come from studies with another,more potent, thromboxane antagonist, BAYu3405, which is currently being evaluated inpatients with asthma.)6

LEUKOTRIENE SYNTHESIS INHIBITORS ANDANTAGONISTSArachidonic acid metabolised via 5-lipoxyge-nase initially forms the unstable LTA4, whichmay be hydrogenated to form the chemotac-tic LTB4; or glutathione is incorporated toform the peptido (cysteinyl) leukotrienesLTC4, LTD4, and LTE4, which are potentsmooth muscle contracting substances. LTC4and D4 are 1000 fold more potent than LTE4,which is in turn 100 times more potent thanhistamine in producing contractions in stripsof human lung.20 The clinical utility of thefirst generation of leukotriene antagonists waslimited by low potency and poor pharmacoki-netics, but more potent compounds are nowavailable-for example, ICI 204219 andMK571. Early studies with these compoundsare very encouraging. For example, in aller-gen challenge studies ICI 204219 reduced theearly phase bronchoconstriction by 80% andlate phase bronchoconstriction by about halfand attenuated the accompanying increase inbronchial hyperreactivity.2' MK571 has alsoshown good results in exercise induced asth-ma.22 Studies in chronic asthma are ongoingand although early reports are encouraging23the role of these agents as anti-inflammatoryagents in chronic asthma remains to bedefined.As LTB4 is a potent chemotactic agent for

inflammatory cells, greater efficacy may come

from compounds that inhibit the enzyme 5-lipoxygenase, thus inhibiting the synthesis ofall the cysteinyl leukotrienes as well as LTB4.One such agent is zileuton (A-64077), whichhas a direct effect on the enzyme.24 Morerecently a compound, MK886, has been

described that has an indirect blocking effectby inhibiting the translocation of the enzymefrom the cytosol to the cell membrane.25These compounds are only partially effectiveat inhibiting leukotriene synthesis in man andappear to have limited efficacy in early clini-cal studies.26 More effective compounds arerequired that will achieve and maintain morethan 90% inhibition of leukotriene produc-tion throughout the dosing period.

PLATELET ACTIVATING FACTOR ANTAGONISTSOf the many mediators suggested to have arole in asthma, platelet activating factor, anether phospholipid released from membranephospholipids by activation of phospholipaseA2, was considered to have excellent scientificcredentials as a potential inflammatory medi-ator, as its effects mimic the pathophysiologyof asthma more closely than any other singlemediator. Exogenous PAF induces profoundbronchoconstriction and bronchial hyperreac-tivity, increases recruitment and activation ofinflammatory cells, increases vascular perme-ability, and induces epithelial damage.2728Extensive research during the 1980s has doc-umented the release of PAF from variouscells, including macrophages, eosinophils(containing the largest quantities), neutro-phils, and platelets. It has shown that PAFnot only releases various mediators andcytokines, including prostaglandins, leuko-trienes, and interleukin-1, but additionallycan prime cells and induce amplification ofinflammatory responses.2829

As the knowledge of the complex interac-tive biological profile of PAF increased, astronger scientific rationale for a role for PAFin the development of the chronic inflamma-tion associated with asthma becameapparent.'0 In response, many companiesfocused on this target and several potent andselective receptor antagonists of PAF are nowavailable and are currently being evaluatedclinically. Data from early clinical studieshave, however, been disappointing. Thusapafant (WEB 2086), given by inhalation31 ororally,32 and oral MK-28733 and UK-74,50534failed to show any effect on antigen inducedearly and late reductions in FEV, or on thesubsequent increase in airway hyperrespon-siveness to agonist challenge.

Data from longer term studies on naturalasthma are awaited. The current view, how-ever, is that inhibition of PAF may not pro-duce effective treatment for asthma, thoughmore potent antagonists with a differentselectivity profile (for example, inhibition ofintracellular as well as membrane extracellu-lar sites) may prove to be of more benefit.

Potential for drug intervention in allergicinflammationThe response of the asthmatic airways toinhaled allergen is extraordinarily complex. Arange of inflammatory cells is known to bepresent in the airways of patients withasthma, including mast cells, macrophages,lymphocytes, and eosinophils.2 A complicated

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network of cytokines and immunologicalstimuli orchestrates recruitment and activa-tion of these cells in response to allergen. Therelease of preformed and newly synthesisedmediators, with attendant epithelial damage,neural stimulation, and plasma extravasation,maintains and amplifies the entire allergiccascade.A scheme of likely events in the allergic

response of the airways is shown in figure 2.Inhaled allergens are ingested and processedby antigen presenting cells (for example,macrophages) and the attendant release ofinflammatory mediators and chemotacticcytokines assists recruitment of other inflam-matory cells to the airways. A specific subsetof T lymphocytes, CD4 T cells, after activa-tion, produce a range of proinflammatorycytokines, which play a part in the recruit-ment and activation of mast cells andeosinophils." Additionally, in response to thedual signal ofT cell contact and interleukin 4(IL-4) B lymphocytes produce antigenspecific IgE.36 This binds, via its Fc portion,to specific high affinity IgE receptors on themast cell surface37 and to low affinity recep-tors on the surface of other inflammatorycells, such as the eosinophil.'8 Re-exposure toantigen cross links the surface bound IgE,triggering cellular degranulation37 and releaseof further proinflammatory mediators andcytokines as well as certain tissue destructiveenzymes and basic proteins.2 The pathophysi-ological responses to this inflammatory cas-

Antigen

Histamine PAFPGs LTsLTs MBPIL-3,4,5,6 ECPProteases

PatemphysologleaEpithelial shedding Plasma extravastionBronchoconstriction Mucus secretion

Neuronal reflexes 1'Figure 2 Mediators released in asthma. PAF-7plateletactivating factor; LT-leukotriene; IL-interleukin; GM-CSF-granulocyte-monocyte colony stimulating factor;PG-prostaglandin; MBP-major basic protein; ECP-eosinophil cationic protein.

cade include shedding of epithelium, extrava-sation of plasma, secretion of mucus andbronchoconstriction, while increased stimula-tion of sensory nerves may evoke release ofbronchoconstrictor and inflammatory neuro-transmitters (for example, acetylcholine, sub-stance P), which further exacerbate theinflammation.2How can the drug discoverer exploit the

knowledge of the early inflammatory events inasthma to design novel, effective drugs for thetreatment of this disease?

There is good evidence, for example, thatintervention by means of a drug directed atthe T cell may offer possibilities for noveltreatment. Activated CD4 T lymphocytes arefound in bronchial biopsy specimens frompatients with asthma in numbers that corre-late with disease severity. Moreover, anincrease in CD4 cells in bronchoalveolarlavage fluid is observed in patients who de-velop a late phase response to allergen chal-lenge.35 Additionally, cyclosporin, which actsmainly through inhibition of activation of Tlymphocytes, showed improved lung functionand steroid sparing effects in chronic severeasthma.'9 Cyclosporin itself, however, hasundesirable side effects (such as nephrotoxici-ty), and improved safety and efficacy profileswould be essential for this novel approach tothe treatment of asthma to be more widelyapplicable.

Inflammatory cell cytokines representanother target for drug intervention as theyhave several key functions; IL-5 and granulo-cyte-macrophage colony stimulating factor(GM-CSF) are important for the differentia-tion, recruitment, and activation ofeosinophils whereas IL-3 and IL-4 influencethe growth and differentiation of mast cells.40IL-4 is also required for IgE synthesis by Bcells.'6 Any one of these cytokines may be atarget for intervention by a novel drug,though rational design of new drugs willrequire still further advances in our basic bio-logical knowledge of the mechanisms ofcytokine production and of their interactionsat specific receptors. Difficult though thischallenge is, it is further complicated by thepleiotropic nature of cytokine action and con-siderable emphasis would have to be placedon identifying new treatments for asthma thatwould not produce unwanted immunosup-pressive effects.

Increased attention is also being given tothe possibility of selectively modulating sec-ond messengers. For example, five isoenzymeclasses of cyclic AMP and cyclic GMP phos-phodiesterases have been defined biochemi-cally4l and, because the distribution ofisoenzymes between different cells varies sub-stantially, an excellent opportunity is avail-able for developing highly isoenzyme specific,and possibly cell specific, phosphodiesteraseinhibitors. Until relatively recently researchinto the potential utility of phosphodiesteraseinhibitors in asthma was confined to the air-way smooth muscle. Certain phosphodi-esterase inhibitors, however, inhibitfunctional responses in some mast cells,

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eosinophils, and lymphocytes.42 Further workis required to identify the functional role ofindividual isoenzymes in different cell types,and this could lead to the development ofbronchodilating and anti-inflammatory phos-phodiesterase inhibitors without the effectson the cardiovascular and central nervous

systems that are produced by the currentlyavailable inhibitors.

Modulation of IgE production or functionhas also been suggested as a possible targetfor intervention.3637 IgE plays a part in propa-

gating the allergic reaction via binding of itsFc portion to specific high affinity receptorson mast cells and basophils. The binding ofIgE does not induce any apparent cell activa-tion, but in sensitised individuals re-exposureto the sensitising allergen cross links the sur-

face bound IgE, triggering mast cell activa-tion and degranulation.37 The mast cell is a

source of a range of-preformed mediators,such as histamine and proteases, as well as

lipid mediators, such as PAF, leukotrienes,and prostaglandins, and possibly also newlysynthesised cytokines, such as IL-3, IL-4, IL-5, IL-6, and GM-CSF.43 Interference withIgE binding or with triggering of cell degran-ulation could lead to novel anti-inflammatorydrugs. Already much is known about how IgEbinds to its receptors, and there is growinginformation regarding the intracellularprocesses that trigger release of mediators.Much more detailed and extensive basicscientific knowledge of these processes is stillrequired, however, and the discovery of newdrugs remains a long way off.

Another potentially important inflammat-ory cell in asthma is the eosinophil.44 Surfacebound IgE molecules may also prime theeosinophil to degranulate in response to aller-gen exposure, though the specific surfacereceptor differs structurally from that on themast cell and has lower affinity for IgE.'8Eosinophils release a mixture of inflammatorymediators and highly basic proteins (majorbasic protein, eosinophil cationic protein)plus oxygen derived free radicals, all of whichmay be associated with the characteristicshedding of epithelium observed in asthma.45Drug strategies targeting the eosinophil may

therefore be beneficial in asthma. As there isan increasing awareness of the role of cell sur-

face adhesion molecules in migration ofinflammatory cells into the tissues, one possi-bility could be to interfere with the migrationof the eosinophil into the airways. Cell ad-hesion and migration are mediated throughseveral different families of adhesion recep-tors. For example, ICAM- 1 (intercellularadhesion molecule 1) is induced andexpressed on epithelial and endothelial cellsin response to certain inflammatory mediatorsand cytokines.46 Indeed, in a primate modelof allergic asthma a monoclonal antibody to

ICAM- 1 reduced infiltration of eosinophilsinto the lungs and bronchial hyperreactivity.46The application of monoclonal antibodies tothe treatment of asthma, which would be anew departure for the drug industry, could beimportant with regard to inhibition of key

processes for which no drug moieties of smallmolecular weight are known.

As the understanding of the pathology ofasthma increases and more is known aboutthe mechanisms of the inflammatory processmore opportunities open up for discoveringdrugs that act at different points in the aller-gic cascade. The table summarises some ofthese possible anti-inflammatory targets;other mechanistic targets have been describedelsewhere.47 There are many exciting andchallenging ideas for the discovery of futuredrugs, but this also poses the dilemma for thedrug discoverer in the pharmaceutical indus-try of how to decide which is the most acces-sible target that is likely to yield a majortherapeutic advance.What intervention will give the best chance

of success in terms of efficacy in treating andpreventing asthma? How can we determinewhat are primary events and what are conse-quences of the disease? Animal models, suchas sensitised guinea pigs and sheep, may helpto guide research, but they do not mimichuman asthma entirely and cannot thereforereliably predict the potential clinical efficacyof drugs. Drug discovery and assessment oftherapeutic potential represent a long andcostly process. For example, it was suggestedin the early 1 980s that PAF may be an impor-tant mediator in asthma,48 but it has taken8-10 years to identify and progress PAFreceptor antagonists and to set up phase IIstudies for assessing their potential efficacy.As the discovery of novel drugs becomes pro-gressively more complex and challenging thetime scale will necessarily lengthen andresearch investment must increase propor-tionally.

Future researchTo reduce the risk of failure and to increasethe probability of designing drugs with activi-ty against asthma we need more knowledge ofthe sequence of events after initiation of theallergic response and the way different media-tors and cytokines interact with each otherand with different cells and of the positiveand negative feedback systems. For example,an antagonist of a particular mediator will be

Possible mechanistic targets for inhibition of theinflammatory cascade in asthma

Drug target Desired action

T cells Inhibition of activation/recruitmentofT cells

InterleukinsIL-3, IL-4 Inhibition of mast cell growth and

differentiationIL-4 Inhibition of IgE productionIL-5 Inhibition of eosinophil activation

and recruitmentIgE Inhibition of binding to mast cells

and eosinophilsInhibition of triggering of mediator

releasePhosphodiesterase Inhibition of inflammatory cell

inhibitors degranulationAdhesion molecules Inhibition of inflammatory cell

recruitment

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effective only if that mediator is released earlyin the inflammatory cascade and contributesin a major way either directly or indirectly,through release of other mediators, in the ini-tiation and propagation of the allergicresponse. Many of the potential mediatorsdescribed presumably do not fall into this cat-egory but contribute variously and indepen-dently to the inflammatory process.

Consequently many drug companies arefocusing on the early events in the allergicresponse to try to increase the chances of suc-cess. Modulation of the function of inflam-matory cells, either directly by targeting cellsor indirectly by inhibiting the production oraction of appropriate cytokines, represents anattractive approach. Selectivity, however,must be feasible-that is, the agent wouldneed to have activity against asthma withoutcompromising other aspects of the immuneresponse.

Undoubtedly over the next few yearsadvances in the knowledge of basic mecha-nisms of the allergic response, at both cellularand molecular level, will play a major part inguiding the discovery of drugs. The futureoffers challenging and exciting opportunitiesand a range of drugs with novel mechanismswill eventually be available for clinical testing.Some of these agents, however, are likely tobe not efficacious antiasthmatic drugs butpossibly important pharmacological tools thatwill help to unravel the complexities of theinflammatory process and basic mechanismsin the pathophysiology of asthma. Furtheradvances in the knowledge of the molecularbiological and cellular processes that underliethe initiation of disease may lead to a new eraof targeting drugs to cure asthma rather thantreating the symptoms.

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Adventitia

Dusts and lungs

Following up a nascent interest in occupa-tional and environmental lung diseases duringmy first few faculty years I embarked on anacademic visit to several centres in Britain. Itwas during the late 1960s, and my "hang-outs" (besides the King's Road) were primar-ily the Brompton, the London School ofHygiene and Tropical Medicine, and theMedical Research Council PneumoconiosisUnit. Britain was a spectacular place forlearning how to investigate occupational lungdiseases. Among many leaders in this fieldwere Richard Schilling and Molly Newhouseat Keppel Street and Gower Street, MargaretTurner-Warwick and Jack Pepys on theFulham Road, and John Gilson and col-leagues in Penarth. Since then, happily, therehave been many opportunities for return visitsand scientific collaboration with overseas col-leagues. I have repeatedly gained knowledgeand insight from these relationships. Here aretwo such examples.

About 10 years ago, my colleagues atTulane and I began a large, multi-mill longi-tudinal study of cotton textile workers in theSouth eastern United States. A major objec-tive was to test Richard Schilling's hypothesisthat, besides periodic symptoms of byssinosis,cotton textile workers were at risk of chronicprogressive airways obstruction. Cumulativedust exposure estimates for each individualwere based on air sampling data and job his-tories. After five years of data collectionanalyses taking smoking into account andusing the individual exposure estimates failedto provide convincing relationships betweendust exposure and annual change in lungfunction. It was time to discuss our difficul-ties with Richard Schilling on my next visit toBritain. By the time we sat down to talk hehad already figured out that we were probablytrying to "fine tune" the individual exposureestimates excessively-beyond the realities ofthe data from mills, where jobs were mostoften not clearly physically separated. He hadcalculated that if the average exposure of themill were assigned to the workers of that millthe dose dependency of the annual change inFEV, was clearly seen in yarn manufacturingworkers, particularly if they smoked.Richard's experience in assessing exposure inan industry that he knew so well allowed us tocomplete the analyses and interpretation and

show the potential for an adverse exposurerelated effect on the airways (in smokingworkers who produced yarn), even at the lowlevels of exposure now mandated by regula-tion.The chest radiograph was recognised as a

useful tool in diagnosing pneumoconiosis inthe 1930s, but its role in epidemiology await-ed the development and several refinementsof a standardised international classification.The resulting system has repeatedly beenshown to quantify responses to (and, ofcourse, retention of) mineral dusts and hasproduced dose-response relationships usefulin the setting of workplace standards aroundthe world. No person has contributed moreto these methods than John Gilson. In myresearch unit it was always a special occasionwhen John was in residence for a fortnight,spending many full days classifying surveyfilms (while Margaret was producing marvel-lous water colours of industrial scenes alongthe Mississippi River). On the occasion ofJohn's last visit, however, he was particularlyunhappy about the technical quality of theradiographs and the variability of this quality,as they had been obtained from laboratoriessituated in the different locations of the man-made mineral fibre plants under study. As wedrove home each evening his frustration wasclear-I, only half jokingly, wondered aloudwhether a bad bout of hay fever and its atten-dant watery eyes, induced by the NewOrleans allergenic environment, contributedto John's poor opinion of the film quality!He was, as usual, absolutely correct, as the

analyses showed unexpectedly high interob-server and intraobserver variability of thereadings, undoubtedly due to the combina-tion of the variable quality and minimalabnormality. His repeated emphasis on filmsof uniformly high quality for epidemiologicalresearch is to be heeded now more than everbefore as investigators survey populations inwhich abnormalities on the chest film are atthe "margin," the central question being "Isthere an effect?"

These have been great years, in no smallway a consequence of the extraordinary pro-fessional guidance that I have received frommy British colleagues.

HANS WEILL

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