Inhaled corticosteroids—Their present and future role in the management of asthma

Review article lnhakd corticosteroids-Their future role in the management

p nt and of wthma

Peter Kiinig, MD, PhD Manhasset, N.Y.

Inhaled corticosteroids have beenusedsuccessfully in the managementof asthma for the last 16 years,’ ever since the discovery of agents with a favorable ratio of topical versus systemic activity, such as beclomethasone dipropionate. They were introduced as offering a safer mode of administration than systemic corticosteroids and were generally consideredsecondline drugs to be usedin patients not controlled by firstline drugs, such as cromolyn sodium or theophylline2 A number of changes in our knowledge about asthmahave occurred in the last few years, resulting in important new questions about the role and appropriate place of inhaIed corticosteroids in therapy. Thus, although in the past the emphasisin asthmawas on reversingthe bronchospasticelement, lately asthma is viewed as a disease in which in&unmation plays an important role.3 This of course emphasizes the importance of corticosteroids because of their antiinflammatory effect. There is now increasing evidence that inhaled corticosteroids can decrease nonspecific bronchial hyperresponsiveness,4s 5 and it has been speculatedthat such an effect can perhaps improve the long-term prognosis of asthma.” An increase in asthma mortality has been reported in a number of countries, and someinvestigators have speculated as to the overuse of bronchodilators and insufficient use of prophylactic drugs, such as cromolyn sodium and inhaled corticosteroids, as a cause of this increased mortality.6 As a result, some authorities advocate the use of inhaled corticosteroids as first-line dtugs.’ In Europe, physicians treating adults with asthma used in-

From the North Shore Universily Hospital, Department of Pediatrics, Pulmonary Medicine, Ma&asset, N.Y. Received for publication March 9, 1988. Acceptad for publication March 16, 1988. Reprint requests: Peter KGnig, MD, PhD, North Shore University Hospital, Department of Pediatrics, Pulmonary Medicine, 300 Community Drive, Manhasset, NY 11030.

haled corticosteroids more often than crurnolyn; and in GreatBritain, inhaled corticoster&ds aremore often used than either cromolyn or tlrsophylline.8 In contrast, some investigators consider that inhaled corticosteroids offer no major advantagesover altemateday prednisone.9.lo To increase further the confusion, a number of new inhaled corticosteroids are now availabie in the United States,and it is unclear whether triamciwlone or flunisolide presents any advantages over heclomethasonedipropionate, the older representative of the group. There is also considerableconfusion about the appropriate dose, dosing frequency. and delivery systemsof inhaled corticosteroids. The aim of the presentarticle is to attemptto clarify some of these issues. SAFETY OF IRJt#Al.ED One of the reasons for the confusion about this fundamental issue is the failure to differentiate between statistically significant ckmges and cIidicalfy relevant side effects. Thus, in one study, serum cortisol and its response to hypoglycemia were significantly lower in a group of children with a%hmatreated with inhaled beclomethasonethan in a co&r01 group without asthma, although the results were still within the normal range.” The authors went on to postulate that this might explain casesof death from presumed adrenal insufficiency described in sevemi children with asthma” fall of whom incidentally were treated with systemic corticosteroids). To take this to the absurd, their conclusion could have been that half the normal population should die every ti.me they have surgery or a serious infection. 299

298

Kdnig

There have been numerous studies of HPA axis function, but very few studies on equally important side effects of steroid therapy, such as osteoporosis, hypertension, and cataracts.The question of how vulnerable to steroid side effects are patients with preexisting psychologic disorders, subclinical diabetes, peptic ulcer, and predisposition for hypertension has not been addressedat all in previous studies. Suppression of HPA axis The first studies, with doses approximately 400 Fgf day of beclomethasone,concluded that there was no suppression.‘j. I4Numerous later studiesconfirmed those original findings”, I6 and demonstratedthat, in patients switched from systemic to inhaled steroids, the HPA axis recovered.“* ‘* However, it was clear from the beginning that with large enough doses, suppression will occur. Thus, Gadie et all9 demonstrated in adults that 1600 p,g/day produced a statistically significant effect on the HPA axis. Messerli et al.” demonstratedthat under special circumstances (last dose administered at midnight), even doses as low as 400 pg of beclomethasonecan cause a significant decreasein the morning cortisol level. As very few patients take their medication at midnight, however, this is hardly of clinical relevance. Although in most studies with up to 400 Fg of beclomethasone, the group mean results did not changefrom baseline. Pour of 10 children in one study did demonstrate some suppression with the metyrapone test.” It is difficult to draw clear-cut conclusions about the dose of inhaled corticosteroids that has suppressive effect on the HPA axis becauseof contradictory results in different studies. Wyatt et al9 demonstrated some suppression in children with 400 to 800 pg (mean 550 pg) of beclomethasonedaily. They concluded that such doses had an additive effect on the HPA axis suppression when they were administered together with alternate-day prednisone at a dosage of 20 to 40 mg. A later study from the same group demonstrated significant suppression in children treated with beclomethasone (532 p,g/day),la compared to control subjects. No data were provided on the normal range in their laboratory, but both morning cortisol and 24hour urinary free cortisol mean values would have been within the normal range of another study, in which adrenalsuppressionwas not found with a mean dose of 490 pg. I6 Both studies from the University of Iowa9*lo concluded that inhaled beclomethasoneand alternate-day prednisoneareequally likely to suppressthe HPA axis. However, in most of the analyses, only the second

J. ALLERGY CLIN. IMMUNOL. AUGUST 1999

day after the prednisone dose was compared, and in those analysesin which the first 24 hours were considered, prednisone causedmore adrenal suppression than inhaled beclomethasone.‘” It is possible that at least part of the suppression in their groups treated with beclomethasonewas due to short coursesof daily prednisone administered for acute exacerbations, whether during the study period10or shortly before.’ Law et al.** studied a group of children treatedwith 300 to 1000 kg (mean 530 p..g)of inhaled beclomethasone.They found that serum cortisol was lower during the night and that the normal morning rise was delayed. In adults, Costello and Clark23found no change in morning cortisol after 1 year of treatment with 1000 pg of beclomethasone. It is possible that more suppressionhas been described in children at similar daily doses because the dose per kilogram weight would be larger in the pediatric population. Sherman et al.,” who could not find suppression in healthy adults treated with 400 or 800 pg/day until the dose was raised to 1600 p,g, analyzed their results in children with asthma and concluded that only doses of 14 pg / kg or larger causedsuppressionthat would not be reachedin adults receiving 800 pg/day. However, our own study with a dose of 13.7I pg I kg / day could demonstrate no adrenal suppression, not only when the group mean was considered but when individual values were examined also. Some patients received 14 p,g or more per kilogram and yet were within the normal range.*6 Whether all these statistically significant changes are clinically relevant is by no means certain, since most of the results were still within the normal range. The danger of life-threatening adrenal insufficiency has probably been overstated. A group of 28 steroiddependentpatients who had an abnormal responseto adrenocorticotropic hormone had major surgery without corticosteroid coverage, and yet none had adrenal insufficiency.*’ However, recovery of the adrenalaxis, when patients receiving systemicsteroidsare switched to inhaled corticosteroids, can be extremely slow, taking up to 3 years and longer.*‘j During this time, patients may be at risk in stressful situations. Another possible problem that has not been addressed so far is whether an HPA axis slightly less responsive to stress will reduce the patient’s natural defensefrom severeacute attacks of asthma. Also, a lower level of serum cortisol at night and in the early morning,22at the time when pulmonary function is at its lowest and when many attacks of asthma occur, may add to the severity and frequency of asthmaexacerbations.

VOLUME 82 NUMBER 2

The effect on growth

Daily administrationof systemiccorticosteroidshas beenassociatedwith serious growth retardation,” and evenalternate-dayprednisoneof as little as 9 mg/day can cause growth suppression.** Most investigators have not demonstratedan effect on growth with inhaled beclomethasonein doses up to approximately 800 ~g/day.‘O~14.29-31 The follow-up in these studies ranged from 1 to 5 years. However, in a group of children followed for 13 years, BalfourLynn3’ found some inhibition of growth in the immediate preadolescentperiod in children treated with beclomethasone at doses >400 p,g/day, although growth in these children caught up later. Littlewood et a1.33 (in a letter to the editor) have describedgrowth retardation in children with asthma treated with jnhaled beclomethasoneat 200 to 800 pg/day (mean 15 Fgikgtday). Thus, although the overwhelming majority of studies demonstrateno effect on growth, some patients, on larger doses,dependentperhapson individual sensitivity, may exhibit some growth retardation. Osteoporosis Reid et al.” studied total body calcium as a measure of total bone mass in adults with asthma. They found that inhaled beclomethasonedipropionate, 400 pg/day, or inhaled betamethasoneisovalerate, 800 p,g/ day, causeda reduction of calcium by 8.8%, comparable to the 9% loss in the group treated with systemic steroids (8.9 mg/day) but administeredcalcium supplement. The loss in the group receiving systemic steroids (6 to 8 mg/ day) with no calcium supplement was considerably more (13.6%). In another study, a group of adults with asthmareceiving daily prednisone (23 mg/day) had 50% less osteocalcin (a marker of osteoblast function) than the control grou~.~~To place these findings in perspective, it is useful to compare them with results found in treating diseasesother than asthma. Gluck et al.,36 in adults with rheumatic disease,found that alternate-dayprednisone (9.4 mg/day) caused osteopenia (increased cortical/trabecular mass ratio) in 32% of patients, whereasdaily administration (mean 12.8 mg/ day) did so in 44% of patients. Ruegsegger et al.“’ concluded that adults with asthma receiving 25 mg of prednisone on alternate days lost 3.5% trabecular bone in 1 year (as assessed by quantitative computed tomography). The loss was age-and-dosedependent, reaching as much as 17% loss in young patients receiving 50 mg on alternate mornings. A dose < 17 mg every other day, resulted in no significant osteoporosis.

inhaled corticosteroids

298

Thus, even though systemic corticosteroids (alternate-dayprednisoneincluded) appearto induce a more profound osteopenia,inhaled ccsrticosteroids are apparentlynot completelyfree of this sideeffect. Since this effect has beenevaluatedin only one study, more such studies are clearly needed, Posterior, subcapsular cataracts Daily administration of systemic eorticosteroids causesposterior subcapsularcataractsin 20% to 30% of patients.‘“. 39Even alternate-dayadministratjon can cause cataracts in 20% of cases, if the treatment is prolonged (more than 2 years).&’A few patients receiving inhaled beclomethasonehave developedcataraCts,‘“~ 4’ although reversalof cataractshas also been describedwhen patients were switched from systemic prednisone to inhaled beclomethasone,” Hematologic changes An increase in neutrophils and total white blood cell count and a decreasein lymphocytes and eosinophils are among the most sensit.ivesystemic effects of inhaled corticosteroids, occurring even at low doses.lo. 20.39.42.43 The clinical relevance of these changesis probably no more than some confusion in the interpretation of hemograms. Other systemic effects In the early days of inhaled conicosteroid usage, fears were expressedthat their prolonged use might causeatrophy of the bronchial mucosa, similar to the long-term effect of topical steroidson the skin. Biopsy specimensof the bronchial mucosahasfailed to reveal such change? and in fact, beclomethasonedipropionate is removed much faster from the bronchi than from the skin. Another frequently voiced opinion was that these drugs may predispose to respiratory infection. Fortunately, this possibility has also proved to be unfounded.4547 Lewis and Cochrane4*described one S/&year-old girl who developed a manic state receiving 200 pg of inhaled budesonide per day. The psychosis was reversed when the dose was reduced to 100 kg/day. Weight gain can occur with systemic corticosteroids, even with alternate-day regimens, but has not been described with use of the inhaled route.” Other corticosteroid side effects, such as hypertension, have not been reported with the inhaled forms.25Hyperglycemia, sometimes caused by systemic steroids, does not occur with inhaled corticosteroids.”

300 Kijnig

Topical side effects Oral candidiasis and dysphonia are much more frequent with use of inhaled steroids than are systemic side effects. Although positive throat cultures of Candida are quite frequent, clinical thrush is generally reported only in about 4.5% to 13% of casestreated with beclomethasone and 4.4% to 10.7% of cases treatedwith triamcinolone.49Most patients with thrush had mild subjective symptoms only. In some studies, hiamcinolone caused less thrush than beclomethasane,” probably becausethe former agentis marketed with a spacer device that reduces considerably the amount of steroid deposited in the pharynx. Thrush affects adults more often than children, is dose dependent, and also dependson the dosing frequency (higher incidence with four times a day than with twice-daily dosing).51 Dysphonia was not affected by dose or dosing frequency in the samestudy. Mouth rinsing can wash out 98% of the amount deposited in the mouth with even large inhaled doses but, interestingly, causes little improvement in the suppression of the morning serum cortisol levels.” This suggests that the systemic effects are caused mostly by the portion absorbed from the lungs and not the portion swallowed from oropharyngeal deposition. Dysphonia hasbeenreportedin 5% to 50% of cases, frequently coexists with candidiasis, but does not appear to be causally related.53Sometimesvoice stress is an important predisposing factor.53In somepatients, dysphonia is associatedwith bilateral adductor vocal cord deformity.54This form is dosedependent,usually not associatedwith candidiasis or voice stress, and probably representsa steroid myopathy. Candidiasis and dysphonia generally respondto treatmentandtemporary lowering of the steroid dose, tend to get better with time, and rarely necessitatewithdrawal of inhaled corticosteroids.‘* The appropriate place of inhaled corticosteroids in the management of asthma After reviewing the various side effects, it is clear that these drugs are not completely innocuous; therefore, their indications versus other drugs has to be basedon a careful risk/benefit analysis in each case. A blanket statement proposing their use as first-line drugs with no relevant side effects is not justified. Inhaled corticosteroids versuscromolyn sodium. In terms of efficacy, some studies have demonstrated beclomethasoneand betamethasoneto be somewhat more effective than cromolyn,55-57although another study found no significant difference.58 The com-

J. ALLERGY CLIN. IMMUNOL. AUGUST 1988

bination of cromolyn sodium with an inhaled corticosteroid appears to be no better than the steroid alone 55, 56. 58 However, the safety record of cromolyn is considerably better than that of the inhaled corticosteroids”; therefore, a trial of cromolyn appearsjustified before the introduction of steroids. Many physicians in Europe and some in the United Statesbelieve that cromolyn is not effective in adults.8v60A review of the literature concluded that, although children respond well somewhat more frequently than adults, a sufficient proportion of adults are successfully controlled by cromolyn to justify a triaL6’ This was amply confirmed by a recent multicenter controlled triaL6* Although cromoiyn sodium is not a direct antiinflammatory agent, its preventive effect includes mediators that are involved in the inflammatory reaction .63This suggests that it exerts a local, indirect anti-inflammatory effect in the airway. Long-term use of cromolyn reduces nonspecific bronchial hyperreactivity,M as do inhaled corticosteroids, although this is to a somewhat lesser extent.65,66One well-controlled study in pollen-sensitive subjectswith asthmahas demonstratedthat cromolyn sodium completely preventedthe seasonalincreasein bronchial hyperresponsivenessto histamine.67This is comparable to the effect of oral methylprednisolone (16 mglday) in a similarly designed study.68 Cockcroft and Murdock69found sodium cromoglycate at least equal to, and in some patients, better than, beclomethasonedipropionate in preventing the increasein nonspecific bronchial hyperresponsiveness occurring after an allergen challenge. Inhuled corticosteroids versustheophylline. The efficacy of inhaled corticosteroids appears superior to that of theophylline,” but the combination is better than the steroids alone.70v 71 Theophylline is a potent drug, administeredby the systemic route, and therefore has many side effects, some of them very serious. Potential problems of memory deficit, poor concentration, depression, behavior abnormality, and poor s&o1 performance raise serious questions about the advisability of longterm therapy with theophylline, especially in children and young adults.72,73 Theophylline has no known effect on the inflammatory componentof asthmaand causesno long-term reduction of bronchial hyperreactivity.74 Rr thesereasons,the argumentsof thoseauthorities who recommend inhaled corticosteroids before theophylline7z7scannot be readily dismissed. inhaled versus systemic corticosteroids. There is

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TABLE I. Systemic

inhaled corticostetords

side-effects

of corticosteroids

Adrenal suppression

Growth retardation

Osteoporosis

++

+++

+++

+++

+

+_ +. ~.

.. _-

+

++

++

++

+

i -f

+ .

+*

5

+t

-r

+

0

0

Daily systemic steroids Alternate-day systemic steroids Inhaled steroids

301

Cataracts

Hematotogic chsnges

Weight gain

Hypert8nsion

-

-

0 = None; + = contradictory data; + = statistically significant, but not clinically important; + + = clinically relevant; f i t := clinically serious. *Probably only at dosesof >5C0 (~gin children and > 1000 pg in adults. ?Only one study published.

little doubt that inhaled corticosteroids are considerably safer than daily administration of oral steroids (Table I). The comparison with alternate-day steroids is a little less one-sided, but the inhaled route is still lesslikely to causeserious systemicside effects. Also, the control of asthma symptoms is better with the inhaled route of administration.*, *’ Practical considemtions inhaled corticosteroids

for the use of

Dose. One of the most frequent mistakes with inhaled corticosteroids is the prescribing of doses too low to be effective. Many physicians try doses, such as beclomethasone,at 300 to 400 pg/day, and if this fails to control symptoms, they switch to systemic corticosteroids. A number of early studiesclearly demonstratedthat beclomethasoneat 800 to 1000 pg daily improved control of asthma, comparedto the usual doseof 400 p,g.2”*76 Later, studieswith budesonidehaveconfirmed the original findings.77,” Some centers have accumulated many years of experience with large groups of patients (mostly adults) treated with 500 to 2000 p,gof beclomethasonedaily andhave found significant improvement over the conventionally recommended doses.79Use of larger doses is made easier in some countries (but not the United States)by the availability of an MD1 that delivers 250 pg per puff. Interestingly, in some patients, the fewer puffs needed with these “forte” inhalers cause less thrush.79The increase in dosecan be achievedsometimeswith surprisingly few additional side effects. Thus, Smith and Hodsons found that at dosesup to 1500 p,g/day of beclomethasone, 9 1% of patients had morning cortisol and responseto adrenocorticotropic hormonewithin the normal range. They found no clinical acute adrenal insufficiency during a 6-year period. Tukiainen and Lahdensuo” compared budesonide at 400 pg with 1600 pg I day, and could find no difference in morning

plasma cortisol. Larger doses also have a more pronounced effect in lowering nonspecific bronchial hyper-responsiveness.*’Therefore, doses should be individually tailored to the patient’s need, and generally control is easierto achievewith somewhatlarger doses (600 to 800 pg of beclomethasone), which can be later reduced to the lowest effective dose Dosing frequency, A number of s&dies found twice-daily dosing equal to, or even better than, the more often used four times a day dosing frequency.**JJ+Gther studies with probably more severe patient populations have demonstratedfour times a day dosing to yield better results, especially at times of relapseof symptoms.52,“+ 86it hasbeen speculated, but not yet proven, that twice-daily dosing would result in better compliance. Some investigators have even claimed that once-a-day dosing is as good as twice-daily and four times a day,*’ but other investigators could not confirm this.***R9 Defivery systems. Unfortunately, most of the innovations in this field are not yet available in the United States.In addition to the MDI with larger doses per actuation, in some countries inhaled corticosteraids are available as a dry powder delivered by turboinhalers (Rotahaler, Glaxo, Inc., ResearchTriangIe Park, N.C.). The advantage is in eliminating coordination problems that are often observed with the MIX. In contrast, the inhalation of a dry powder may causemore cough and wheeze. Inhalation of the dry powder formulation appearsto be as effective as the MDI.%x91 Infants and young children cannot use MDIs or Rotahalers. A number of articles have been published abroad on nebulized solutions of beclomethaNebulizer solution of beclomethasoneis not sone.92-94 available in the United States,but some investigators have used via power-driven nebulizersI a flunisolide solution marketed for nasal use.9s Spacerdevicesreduce oral deposition and therefore

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TABLE II. Relative potencies of topically selective glucocorticosteroids in inhibiting rat or mouse ear edema formation and thymus involution after topical application

Compound

Budesonide Beclomethsone dipropionate Flunisolide Triamcinolone acetonide

Topical anti-inflammatory potency

Systemic potency

Ratio of topical to systemic potency

1 0.4

1 3.5

1 0.11

0.7 0.3

12.8 5.3

0.05 0.05

From reference 44.

the prevalence of thrush.%At the sametime, probably by better pulmonary deposition, control of asthmais improved also.% A number of types of spacersare available in the United States, ranging from tube spacersto a largevolume collapsible bag. The relative merits of different spacershave been reviewed elsewhere.97 Which inhaled corticosteroid should you choose?

In addition to beclomethasonedipropionate, which was the first of the inhaled steroids to be marketedin the United States, triamcinolone acetonide9**w and flunisolide’W~‘*’ are also available now. In Europe and elsewhere, budesonidee6,lo2is quite widely used. The risk-to-benefit ratio of these drugs mostly depends on their ratio of topical to systemic potency. This ratio is most favorable for budesonide, followed by beclometbasone,and the least favorable with flunisolide and triamcinoline, which are about equaP (Table II). To confuse further the issue, triamcinolone and budesonide are marketed with a spacerdevice, whereas flunisolide is advertised by the manufacturers as a long-acting drug (twice-daily administration). The only drug that has been compared fairly extensively with beclomethasoneis budesonide.Despite a topical activity (measuredby skin vasoconstriction) that is twice that of beclomethasone,” most studies have failed to demonstratea better clinical response to budesonide.103-105 A few studies have demonstrated advantagesfor budesonide,‘06-‘08 but one trial found beclomethasonemore effective in reducing the prednisone dose.lWMost of these studies did not include completely comparable situations for the two drugs becausebudesonide was administered with a spacer, whereasbeclomethasonewas not. There are very few studies comparing beclometh-

CLIN. IMMUNOL. AUGUST 1988

asonewith flunisolide, and none with triamcinolone. Gale et al.“* comparedflunisolide at 1000 pg / day (in two doses) and beclomethasoneat 400 Fg/day (in four doses). Physician rating was better with beclomethasonein six patients, whereas only one patient did better on flunisolide. Nevertheless, none of the differences were statistically significant.

Dry et al.“’ also used flunisolide, 1000 pg/day, and beclomethasone,400 p,g/day and found statistically significant differences in favor of flunisolide in four of 10 analyses. However, symptoms were not

recorded in diaries, and most analyseswere basedon overall patient and doctor assessments,which are not very reliable criteria. The most reliable measurement in the study, the twice-daily peak expiratory flow measurements, failed to demonstratea significant difference between the two agents. Thus, at this point, the only inhaled corticosteroid that has someadvantagesover beclomethasoneis budesonide, but it is not available currently in the United States. There is no evidence that either flunisolide or triamcinolone are either more potent or safer than beclomethasone, although the triamcinolone inhaler might be less likely to cause cough.1’2 Flunisolide is no more longer acting than the other agents. The advantage of the spacer, which is marketed together with triamcinolone, can be easily overcome by use of a spacerwith beclomethasone.However, not all patients need a spacer.“3 In conclusion, inhaled corticosteroids are clearly not completely free of side effects, both topical and systemic. Therefore, they should not be automatically substituted for all presently used first-line drugs without careful risk-benefit analyses. Cromolyn sodium has far fewer systemic side effects. Therefore, a trial of this nonsteroidal agent is justified before resorting to an inhaled corticosteroid. In my opinion, this applies to both children and adults. The comparisonwith theophylline is more difficult to decide with the present evidence, and the choice between them remains a judgment call. By contrast, the side effects of inhaled corticosteroids are less than those incurred when the sytemic route (alternate-day administration included) is used and are certainly a lesser evil than poorly controlled asthma, which is a cause of increasedmorbidity and mortality. All too often physicians are still afraid to use inhaled corticosteroids, or adequatedosesof these, resulting in dangerously undertreatedpatients. The optimal place of inhaled corticosteroids in the future is very exciting. It has been speculatedthat by their effect on inflammation and their ability to reduce

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the basic defect of asthma, namely, bronchial hyperresponsiveness, inhaled corticosteroids might improve the long-term prognosis of the disease.3 If this potential should be confirmed by future research, the traditional role of these drugs in the management of asthma will have to reevaluated. Perhaps new drugs, with better topical-to-systemic ratios will be discovered, although thus far this search has been rather disappointing. Some drugs with exceptionally low systemic activity, such as fluocortinbutylester,24. IL4 have failed to be clinically useful drugs.

The author wishes to thank Mrs. Theresa Battaglia, for typing the manuscript. REFERENCES

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