Assessment of oral antiasthmatic drugs by inhalation challenges

Assessment of oral antiasthmatic by inhalation challenges Constantine

J. Falliers,

M.D. Denver,

Elective inhalation of incremental doses of aerosolized allergenic extracts by sensitive subjects results in fairly reproducible bronchoconstriction and thus can be useful in the detection of etiologically significant airborne allergens. ’ 2 Another application of bronchial inhalational tests is the demonstration of a possible protection against induced bronchoconstriction by pretreatment with systemic or topical antiasthmatic drugs .:l. 4 Obviously, the meaningful interpretation of both the detective and the protective tests is entirely conditioned by (1) the criteria for the selection of subjects to be tested, (2) the type and dose of the antigens to be inhaled, and (3) the methodology and timing of the pulmonary function tests, including the question of what is defined as a “positive” immediate or late response.“-’ Furthermore, the protective effect of individual pharmacologic agents and their possible combinations can be assessed correctly only if guidelines can be established regarding (1) the dosage of the drug to be administered, (2) the route and timing of treatment, and (3) a possible dose-response range, relating the required therapeutic levels of the drug to the total amount of the inhalational antigenic challenge. It must also be recognized that, somewhat paradoxically, the clinical efficacy of certain drugs and their capacity to block inhalational challenge responses do not correlate.” For instance, corticosteroids (Table I), which are almost invariably effective in suppressing asthma, do not protect against inhalation provocation tests. On the opposite side, cromolyn sodium, which can block experimentally induced bronchoconstrictive reactions to inhaled allergens,* is therapeutically inconsistent or totally ineffective. Atropine-like, anticholinergic drugs have been the subject of conflicting reports but generally do not seem to ensure protection against bronchial challenge ,4. !) and only the adrenergic agonists and the methylxanthines appear to inhibit bronchial responses to inhaled antigens to a degree commensurate with their known clinical efficacy.” The studies to be pre-

From the Allergy and Asthma Clinic. Reprint requests to: Constantine .I. Falliers, M.D., Allergy and Asthma Clinic. 155 Cook St., Denver, CO 80206. 0091-6749/79/130685+04$00.40/0~

1979The

drugs

Co/o.

Special abbreviations used R,,.: airway resistance SR,,, : specific R,,, V,,: volume of thoracic gas

FEV,: I-set forced expiratory volume FEFt5--75: forced expiratory flow at 25% to 75% PEFR: peak expiratory flow rate

TABLE I. Divergent challenge

clinical and inhalation effects of antiasthmatic medication

Drug category

Clinical efficacy

Bronchial challenge inhibition

Adrenergic agonists

++

++

Anticholinergics Corticosteroids Cromolyn sodium Methylxanthines

++ +++ + or0 ++

+ or 0 0 +++ ++

Legend: + + + , excellent; + +, good; +, fair; 0, none.

sented pertain to the latter 2 categories of antiasthmatic drugs and represent 2 investigational phases: I, a comparison of single-entity ephedrine and theophylline with their combination, in fixed doses; and II, an evaluation of 3 different doses of a single preparation, oxtriphylline elixir. MATERIALS

AND METHODS

The young adults, who voluntarily participated in these

studies, were known to be highly sensitive to seasonalpollen allergens, having had intense upper respiratory symptoms of pollinoesis and having been shown to have high titers of reaginic antibodies. Clinically, all these patients had experienced episodic wheezing during the pollen season, but had no evidence of persistent asthma and had required no regular medication for bronchial airway obstruction. The details of their selection and testing procedures have already been presented.” Baseline spirometry was essentially normal and plethysmographic measurements showed only minimal elevations of airway resistance (R,,Y) not associated with any clinical ventilatory impairment (Table II). Plethysmography was preferentially employed for the studies for 2 main reasons: (1) its relative indepen-

C. V. Mosby Co.

Vol. 64, No. 6, Part 2, pp. 685-688

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J ALLERGY

TABLE II. Demographic

and clinical

data on 6 persons tested with inhalation

Baseline Patient

Sex

Age (vr)

S. B.

F

P. W. S. E. R. F. 1. L. G. A.

F

24 23 34 44 38 35

F

F F M

pulmonary

PER CENT

challenges

function

R,, (cm H,O/l/sec)

3.88 2.79 3.16 3.12 3.42 3.13

Vt, (ml)

Antigenic challenge (1 : 200 w/v aqueous solution)

3,892 3,456 4,306 3,510 3,027 4,889

Grass pollen (timothy, Kentucky blue, orchard) Grass pollen (timothy, Kentucky blue, orchard) Grass pollen (timothy, Kentucky blue, orchard) Ragweed (giant and short) Sage (common) Ragweed (giant and short)

TABLE Ill. Relative

significance of spirometric and plethysmographic changes

INCREASE IN Raw AFTER BRONCHIAL CHALLENGE 130

CLIN. IMMUNOL DECEMBER 1979

FEV,, FEF,,-,,,

ANTIGEN ALONE

120

I

110

PEFR, etc.

II

Ill

25%

33%

75% 50% 25%

70

~ -50%

60

II

Ill

400%

420%

400% ~ 800%

90% __ 770%

500% 25%

80

I

120%

100 90

SRWJ

50% _____ -66%

800%

Legend: A bronchial inhalation challenge, if positive, will lower

/

50

THEOPHYLLINE

40

/EPHEDRINE

(TH)

(E)

30 20 IO 0 CHALLENGE

lo’

20’

t (one hour after drug intake) TIME (MINUTES) FIG. 1. Inhibition of antigen-induced asthma with oral ephedrine, theophylline, and phenobarbital, alone or in combination.

dence from maximal subjective effort and (2) the relatively wide scale of variability upward (Table III), which appeared preferable to the downward and more limited change in spirometric Bow measurements. Baseline data were obtained before and after inhalation of isotonic buffered saline aerosols and appropriate allergenic solutions. After negative saline controls and reproducibly positive (100% increases in R,,,) allergenic challenges were observed, the patients were scheduled for successive visits, at least 3 days apart, during which the therapeutic trials were conducted. In phase I, a double-blind, randomized comparison was conducted of 5 apparently identical tablets containing (1) 24 mg ephedrine; (2) 130 mg theophylline; (3) 24 mg ephedrine and 130 mg theophylline; (4) same combination plus 8 mg phenobarbital, i.e.. the standard Tedral formulation, and (5) placebo.

flow rates (limit: 0) and increaseairway resistance(limit: infinity) in percentageswhich will appear different if expressed(1) on an actual scale of percent predicted, (II) as a ratio of change predicted, and (III) as percent of baseline values. The aerosolized allergenic challenge was conducted 1 hr after drug administration and was followed by pulmonary function tests repeated at 10, 20, 30, 60, 120, and 180 min. The same methodology was observed in phase II, during which the treatments consisted of single doses of oxtriphylline elixir (supplied as Choledyl by Parke-Davis, Morris Plains, N. J.) calculated to deliver 2, 4. or 8 mgikg to each subject. A nurse administered these treatments in random sequence, without the knowledge of the pulmonary function technician, thus setting up a “blind observer” situation. All patients were instructed to report adverse and beneficial reactions that occurred after leaving the research laboratory.

RESULTS No significant protection attributable to placebo was noted among the patients tested in phase I. In fact, on 5 occasions following administration of placebo, the test had to be interrupted with the inhalation of a bronchodilator isoproterenol aerosol, 250 ,ug, because of increasing discomfort from asthma. By contrast, ephedrine and theophylline, each separately, prevented to a significant degree the increase in R,,. and SR,,. (R,,. x V,) following the allergenic inhalation challenge. The combination of ephedrine and theophylline, whether without or with

VOLUME NUMBER

Assessment

64 6, PART 2

80

I! -

+ /I

ti 7

;1 /

-

-

FIG. 2. Inhibition

of antigen-induced

drugs

687

PLACEBO

I

c

MINUTES

/4 f//

of oral antiasthma

I

PAST CHALLENGE asthma

the addition of phenobarbital (i.e., Tedral), was shown to be even more effective than either of the active components alone in blocking the allergen-induced ventilatory impairment (Fig. 1). Indeed, under the conditions of this experiment and for the selected subjects tested, pretreatment with this standard combination of ephedrine and theophylline, 1 hr before challenge appeared to be sufficient to prevent any significant change in R,, and V, and any clinical evidence of asthma, without producing any noticeable side effects. No delayed reactions, either to the allergenic challenge or to the drugs administered, were reported by any of the participants. No significant changes in baseline values for R,, and V, were noted from 1 testing day to another. Phase II data, likewise, showed a physiologic stability of the baselines in pulmonary function, as was expected for individuals without any history of unpredictable paroxysms of asthma. At 10 min postchallenge, i.e., 70 min after administration of oral elixir (delivering 2, 4, or 8 mgikg oxtriphylline, or placebo), the mean changes in R,, (Fig. 2) were not statistically significant. However, at 20 min after challenge, the increase in R,,,. following all treatments, including placebo, was significantly smaller than that induced by the allergen aerosol alone, without any premeditation. The 8 mg/kg dose of ox-

by oxtriphylline.

SEW

THEB~PIUINE: a

lo-

l+dM.

2, 4, or 8 mglkg.

X: hWAYS

kSISTbfKE(~~:Aw)

PERCENF Cf BASELIK INCREASE

x.0

II2-

-/

k--.

x0

tM

0 --.--__-. - ____-- -__-_______-___-- __--._________--___--___- ____- ____ 0 2

l

Pt0.05

6

4 b.AL

bC”?lPHYLLlNE

VS. hAcEB0;

bSE

f: P<0.05

( h,LEDYL

a &KG hlXiR

)

Vs. AVG. FOR 2 V&KG.

FIG. 3. Dose-related responses to oxtriphylline: serum theophylline 90 min after oral medication and airway resistance 30 min after pollen inhalation test, conducted 60 min after medication.

triphylline inhibited the response to the allergenic challenge significantly more than the 3 other treatments, namely, 2 mgikg, 4 mg/kg, and placebo. Similarly, at 30 min postchallenge, all treatments including placebo showed an inhibition of the bronchoconstrictive response in comparison to no treatment and the differences were statistically significant (p < 0.05). At that time the 3 doses of oxtriphylline produced results statistically superior to placebo results, but the doses showed no differences in ability to

666

Falliers

block the allergen-induced increases in airway resistance. Blood theophylline levels were measured during the phase II tests before drug administration, 1 hr later (immediately before bronchial inhalational challenge), and 30 min following challenge. The mean serum levels at the time of the challenge, i.e., 60 min after drug intake, were 3.8 pg/ml for the 2 mgikg dose; 7.3 kg/ml for the 4 mglkg dose; and 10.8 pgiml following the 8 mgikg dose of the elixir. Thirty minutes later, the mean levels dropped to 2.8 pgiml, 5.5 pgiml, and 9.5 pgiml for the 2, 4, and 8 mgikg doses, respectively. The relationship between oral dosage and serum theophylline levels 90 min after oxtriphylline intake is shown graphically in Fig. 3. The figure also shows the correlation between raised serum theophylline level and inhibition of the bronchoconstrictive reaction to the inhaled allergens. The increase in R,,,. tapered as the level of serum theophylline was raised toward a level considered adequate and generally safe for therapeutic purposes. CONCLUSION Bronchial inhalational challenge tests have been found capable of demonstrating differences in the antiasthmatic effect of oral drugs, which can be considered relevant in clinical therapeutics. A standard combination of the well recognized oral bronchodilators, ephedrine and theophylline, was shown to be more effective than either of the ingredients alone in preventing the increase in specific airway resistance provoked by the inhalation of appropriate aerosolized allergenic solutions. Three incremental doses of a single-entity methylxanthine compound, oxtriphylline elixir (Choledyl). were likewise effective in blocking

J. ALLERGY

CLIN IMMUNOL DECEMBER 1979

allergen-induced bronchoconstriction and the protective effect was correlated with the level of serum theophylline attained after each of the treatments. Thus, experimentally induced bronchoconstriction may be considered an acceptable and objective approach to the evaluation of new and old antiasthmatic drugs and has the advantage of greater quantitative sensitivity and elective reproducibility, in comparison with naturally occurring bronchial allergic reactions. REFERENCES 1. Cardoso RR de A, Falliers CJ: Inhalation bronchial challenges with house dust antigen: Technique, reactions. comparison with the results of skin tests. Acta Allergy 29: 1. 1974. 2. Cardoso RR de A: Cutaneous and mucosal allergy tests in viva, in Falliers, CJ, editor: Clinical allergy. New York, M. Dekkrr. (In press.) 3. Falliers CJ, Katsampes CP: Pharmacologic modification of induced asthma. Ann Allergy 36~99, 1976. 4. Fish JE, Rosenthal RR, Summer WR, Menkes H, Norman PS, Permutt S: The effect of atropine on acute antigen-medicated airway constriction in subjects with allergic asthma. Am Rev Respir Dis 115:371, 1977. 5. Pepys J, Hutchcroft BJ: Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 112:829, 1975. Pepys J: Clinical and therapeutic significance of patterns of allergic reactions of the lungs to extrinsic agents. Am Rev Respir Dis 116:573, 1977. Permutt S. Rosenthal RR, Norman PS, Menkes HA: Bronchial challenge in ragweed-sensitive patients, in Lichtenstein LM, Austen KF, editors: Asthma: Physiology, immunopharmacology and treatment. New York, 1977, Academic Press. pp. 265-28 1. Falliers CJ: Cromolyn sodium (disodium cromoglycate) prophylaxis. Pediatr Clin North Am 22: 141, 1975. Rosenthal RR, Bleecker ER, Laube B, Norman PS, Permutt S: Cholinergic response to histamine challenge. J ALLERGY CLIN IMMUNOL 61:139. 1978.