EVALUATION 'OF THERAPEUTIC SUBSTANCES THE RELIEF OF€¦ · EVALUATION'OF THERAPEUTIC SUBSTANCES EMPLOYED FOR THERELIEFOFBRONCHOSPASM. V. ADRENERGICAGENTS By ELLIOTT BRESNICK,2 JOHN

EVALUATION'OF THERAPEUTIC SUBSTANCESEMPLOYEDFORTHERELIEF OF BRONCHOSPASM.V. ADRENERGICAGENTS

By ELLIOTT BRESNICK,2 JOHN F. BEAKEY,3 LEON LEVINSON,'AND MAURICES. SEGAL5

(From the Department of Inhalational Therapy, Boston City Hospital, and the Department ofMedicine, Tufts College Medical School, Boston)

(Received for publication March 31, 1949)

Many laboratory techniques have been em-ployed in the study of sympathomimetic amines,particularly in an attempt to correlate chemicalstructure with pharmacological activity (1-7).In Table I are shown the structural formulae ofthe preparations dealt with in this report.

The technique of protection studies in asthmatichuman subjects appears to offer an additionalmethod of investigating and evaluating these andother substances in the ultimate test object, man.The technique essentially consists of the measure-ment of the protection afforded by any substanceagainst the dyspnea and bronchospasm induced byrepeated administrations of histamine, methacho-line, or allergens, as measured, in part at least,by changes in vital capacity.

METHODS

The methods we have employed and their historicaldevelopment have been extensively presented elsewhere(8, 9).

In the experiments reported at this time, the broncho-spastic agents used were histamine diphosphate 6 andmethacholine chloride employed intravenously or asaerosols. The protecting ability of the therapeutic agentunder examination was determined by serial observationsof the reduction in vital capacity produced by repeatedadministration of a constant dose (predetermined as cap-able of producing a consistent reduction in vital capacity

1 This study was supported by a grant from the UnitedStates Public Health Service.

2 Out-Patient Physician, Boston City Hospital; FormerCharlton Research Fellow and now Assistant in Medi-cine, Tufts College Medical School.

8 Research Fellow in Medicine, Tufts College MedicalSchool.

4Assistant in Medicine, Tufts College Medical School.6 Director, Department of Inhalational Therapy, Boston

City Hospital; Assistant Professor of Medicine, TuftsCollege Medical School.

* Kindly supplied by Abbott Laboratories, Inc., Chi-cago, Illinois.

7Kindly supplied by Merck and Company, Rahway,New Jersey.

of at least 25 per cent) of histamine or methacholine atvarying intervals after the protecting agent was admin-istered. The degree of protection may be described interms of the following equation:

p CC E X 100,Cwhere P is the degree of protection in per cent, C thecontrol drop in vital capacity produced by administrationof the bronchospastic substance (before the protectingdrug is given), and E the drop similarly produced at anytime after the protecting agent has been administered.These percentage values may then be massed into aver-ages derived from several experiments on different asth-matic subjects. Determination of such averages is neces-sary, for we have repeatedly encountered single protec-tion studies, or even repeated studies in the same indi-vidual, which were at variance with the average of resultsobtained by employing the same drugs in many experi-ments carried out on many individuals.

RESULTS

1. Epinephrine hydrochloride. Epinephrine hy-drochloride 1: 1000, 0.5 cc. subcutaneously, causethe usual side-reactions of throbbing in the chestand head, uneasiness, tremor, etc. Protection wasstriking, however, in that this dose afforded 100per cent "immediate" (five to ten minutes afterinjection) protection against intravenous hista-mine. This decreased gradually reaching a levelof 40 per cent after 143 minutes (Figure 1).This 40 per cent level has previously (9) beenproposed as the minimum at which protectionmay be considered significant, in view of the er-rors inherent in any technique of clinical assay.Against the bronchospastic effects of methacho-line, epinephrine hydrochloride 1: 1000, 0.5 cc.subcutaneously, provided 90 per cent immediateprotection and maintained a significant level, over40 per cent, for 83 minutes. These results arepresented in tabular form in Table II.

Subcutaneously administered epinephrine wasalso assayed against the bronchospastic effect ofaerosols of histamine and methacholine and dis-

1182

STUDY OF ADRENERGICAGENTSFOR RELIEF OF BRONCHOSPASM

TABLE I

Structural relationships of the sympathomimetic agents studied. (Modifiedfrom Gunn [3])

CH-CH-NH

NEOSYNEPHRIN H OH H OH H CH3

EPINEPHRINE OH OH H OH H CH3

VAPONEFRIN OH OH H| OH H CH3

ISUPREL OH OH H OH H HCeCH3EPHEDRINE H H H OH CH3 CH3ORTHOXINE H H OCH3 H CH3 CH3

Vaponefrin is a specially prepared racemic epinephrine.

played somewhat less, though still very effectiveprotecting ability. Against histamine it showed70 per cent immediate protection, which rose to apeak of 86 per cent at 40 minutes, and maintaineda level greater than 40 per cent for 127 minutes.Less protection against methacholine was againobserved; there was an immediate level of 40 percent, rising to a peak of 51 per cent at 38 minutes,and remaining at a significant level for 72 minutes.

The 1: 100 dilution of epinephrine hydrochloride(10) was dispensed in a glycerine-water solution,as were all other agents employed as aerosolizedmists. Deep inhalations at ten-second intervals

EPINEPHRINE HCL 1:100005CC. SC.

---SuSTAMINE IV CT~tIALS)-IECHOLYL IV (IT*ALLS-*.-"STAM1NC AERCWAiALS)-X -ECHOLYL AZRC4TMIALS)

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were administered with a standard Vaponefrinhand-bulb nebulizer until six were completed.Against intravenous histamine 75 per cent im-mediate protection was observed. The signifi-cant level of 40 per cent lasted for 28 minutes.Against intravenous methacholine there was 56per cent immediate protection and an 18 minuteduration of the 40 per cent level (Figure 2).

The protective capacity of epinephrine aerosolappeared slightly greater when assayed againstnebulized bronchospastic agents. There was 89per cent immediate protection and 36-minuteduration of the 40 per cent level against histamine;

100-

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FIG. 1. THE PROTECTION AFFORDEDAGAINST HISTAMINE AND METHACHOLINE (REFERRED TO ABOVE ASMECHOLYL) BY 0.5 CC. OF EPINEPHRINE HYDROCHLORIDE1: 1000, AND 0.3 CC. OF 1 PER CENT NEOSYNEPHRINADMINISTERED SUBCUTANEOUSLY

1183

ELLIOTT BRESNICK, JOHN F. BEAKEY, LEON LEVINSON, AND MAURICE S. SEGAL

TABLE II

Summary of the pertinent data obtained with the phenylethylamines when tested against the bronchospastic effectsof histamine and methacholine (referred to below as mecholyl)

BRONCHOCONSTRICTINGAGENTI *1 7

PROTECTING IMMEDIATE DURATION OF IMMEDIATE DURATION OF IMMEDIATE DURATION OF IMMEDIATE DURATION orPROTEING PROTECTION IGNiFICANT (40 PROTECTION NIFICANT C40 PROTECTION SIGNIFICANT C40V PROTECTION SIGNIFICANT (4¢X,DRUG (96) PROTECTION C(%) PROTECTION (96) PROTECTION (26) PROTECTIONDRUG (6) I(MINUTES) (MINUTEs) (MINUTES) (MINUTES)

PINEPHRINE 100 143 90 83 70 127 40 72EPINEPHRINE 75 28 56 IS 89 36 66 17

1:100 AER. __ _ _ _ __ _ _ _ __ _ _ _ _ _ _ _ _VAPONEFRIN 93 27 74 18 90 53 87 402.25 %_AER._____ ____NEOSYNEPHRIN 13 0 13 0

1:100, 0.3CC., S .NEOSYNEPHRIN 52 16 32 0

1:100 AER. __________

ISUPREL ~~98 82 91 811:100 AER. __________

| ISUPREL 708 22 69s 42 | 84 | 21 65s 25ISUPREL

I.200A HISTAMINE IVMEH 4YI2 HITAIEE.4EHOY2AR

1:00,oSUPRELs 100 30 56 1 8 ___

and 66 per cent immediate and 17-minute dura-tion of the 40 per cent level against methacholine.These data are not, however, significantly dif-ferent from those obtained with the intravenousbronchospastics.

2. Vaponefrin.8 This is a 2.25 per cent solu-tion of a specially prepared synthetic racemic epi-nephrine. Richards, Barach and Cromwell (11)considered it preferable to the official 1: 100 solu-tion of epinephrine hydrochloride, which is thelevo-rotatory isomer. We have compared theseaerosols elsewhere (12).

Using histamine intravenously we found thatsix deep inhalations of Vaponefrin aerosol pro-vided 93 per cent immediate protection and sig-nificant protection (over 40 per cent) lasting 27minutes. Against intravenous methacholine weobtained an immediate level of 74 per cent and aduration of a significant level of 18 minutes. Em-ploying the bronchospastics by nebulization re-sulted in no greatly significant difference in in-tensity of action, 90 per cent against histamine and87 per cent against methacholine. However, the40 per cent level was maintained definitely longer,53 minutes with histamine and 40 minutes withmethacholine (Figure 2). The explanation forthis discrepancy is obscure; it may simply be dueto inadequate sampling.

8 Kindly supplied by the Vaponefrin Co., Upper Darby,Pennsylvania.

3. Neosynephrin. As may be seen from TableI, this drug differs from epinephrine only in theabsence of the para-hydroxyl group on the aro-matic portion of the molecule. The compoundsresulting from removal of one or both hydroxylgroups are more stable but have greatly decreasedinhibitory effects. Various investigators (11, 13-15) have found neosynephrin of little value as abronchodilator although it may be an efficientbronchovasoconstrictor (14, 15).

Utilizing the 1: 100 solution of neosynephrin,we have studied the protecting effect of the drugadministered by nebulizer and by hypodermic in-jection. Our studies were limited to intravenoususe of the bronchospastic agents. Figure 1 por-trays the ineffectiveness of 0.3 cc. subcutane-ously, the level of protection never exceeding 20per cent. Neosynephrin aerosol, 1: 100, in theusual dose of six deep inhalations, proved some-what more effective (Figure 2), displaying againsthistamine 52 per cent immediate protection whichdropped below 40 per cent within 16 minutes.Against methacholine no significant protectivelevels were attained, 32 per cent being the highestobserved.

4. Isuprel.9 This sympathomimetic amine,1- (3,4-dihydroxyphenyl) -2-isopropylaminoethanoldiffers from epinephrine only in the alkyl group

9Kindly supplied by Winthrop-Stearns, Inc., NewYork, New York.

1184

HISTAMINE AER.HISTAMINE I.V MECHOLYL I.V. MECHOLYL AER.

1185STUDY OF ADRENERGICAGENTSFOR RELIEF OF BRONCHOSPASM

VAPONEFRIN6 INHALATIONS

---NHISTAIAR IV CS TRIALS I-MCC"OLYL IV CS TRTALS )-.-ViSTASMIC AMCR4TRIALS )

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FIG. 2. THE PROTECTIONNOTEDAGAINST HISTAMINE AND METHACHOLINE(REFERRED TO ABOVE AS MECHO-LYL) BY NEBULIZED SOLUTIONS OF EPINEIHRINE HYDROCHLORIDE(1: 100), VAPONEFRIN (2.25 PER CENT) ANDNEOSYNEPHRIN(1 PER CENT)

attached to the nitrogen atom (Table I). It hasbeen demonstrated that substitution on the aminonitrogen of branched alkyl groups, particularlyisopropyl (as in Isuprel) and terbutyl, producescompounds with enhanced sympathin I-mimeticproperties (4-7, 16). The specific structure ofthe substituted alkyl group is also important ininfluencing the inhibitory potency of such com-pounds.

The clinical efficacy of Isuprel has been previ-ously reviewed by Segal and Beakey (17, 18),who introduced its use in this country. Cohenand Van Bergen (19) have found Isuprel a mosteffective antagonist of methacholine-inducedbronchospasm in animals and of spontaneousasthma in man.

Wehave employed a 1: 50,000 dilution of Isu-prel intravenously in a few subjects with variableresults. Occasionally the most dramatic possiblecomplete relief of clinical asthma has been noted,while a dose of 0.25 cc. (0.005 mgm.) was still be-ing administered. The effect persisted for a mat-ter of hours. In other instances relief was onlypartial and transient after intravenous administra-tion of 0.25 cc. (0.005 mgm.) to 0.5 cc. (0.01mgm.), even in repeated doses. The 0.25 cc.dose caused a uniform increase of 20-30 beatsper minute in the heart rate. All patients ex-perienced unpleasant, although not alarming, pal-pitations. The 0.5 cc. dose, on the other hand,accelerated the pulse by 50 beats per minute andcaused uneasiness and alarming palpitations. The

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effect on blood pressure was minimal. The doseof 0.005 mgm. appeared to cause a small increasein systolic pressure (approximately 10 mm. ofmercury), probably due mainly to the increasedrate. There appeared to be, in general, a tend-ency toward a slight fall in the diastolic level.The larger dose, 0.01 mgm. (0.5 cc.), caused atransient drop in systolic and diastolic levels si-multaneous with the greatest increase in heartrate. We performed several protection studiesusing this very dilute solution of Isuprel intra-venously. Doses of 0.25 cc. (0.005 mgm.) and0.5 cc. (0.01 mgm.) failed to demonstrate any pro-tective ability against histamine or methacholinefor long enough periods to be measured by themethod employed.

Isuprel 1:100, the dilution commonly employed

with epinephrine, provided essentially completeimmediate protection against intravenous hista-mine and methacholine (98 and 91 per cent re-spectively). Not only did it maintain a signifi-cant (40 per cent) protection against histaminefor 62 minutes, but it also afforded a surprising81-minute duration against methacholine (Figure3). However, this dilution of Isuprel frequentlycaused unpleasant epinephrine-like side-effects.

Isuprel 1:200 is the dilution in common usefor nebulization. It is, of course, one-half as con-centrated as the usual epinephrine solution andequivalent to approximately one-third the con-centration of levo-epinephrine in Vaponefrin.This dilution of Isuprel displayed (Figure 3) 70per cent immediate protection against intrave-nous histamine with a duration of 22 minutes for

ISUPRELt5OOO 05C.C. SC.--4IISTAMIN AI.V. (6 TRIALS )-MECHOLYL 1.1 C( TRIALS )

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1186

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significant levels. Against intravenous metha-choline, there was a 69 per cent immediate leveland significant levels persisted for 42 minutes.As may be seen in Table II, the data were, withone exception, essentially equivalent when thebronchospastics were employed in the form ofaerosols. An immediate level of 84 per cent anda 21-minute duration of significant protection werefound against histamine; and 65 per cent with 25minutes were the comparable values for metha-choline. The only discrepancy appears in theduration of levels over 40 per cent against metha-choline administered intravenously and as anaerosol. This, again, may be due to inadequatesampling and the consequent chance inclusion ofpatients with extreme differences in responsive-ness to Isuprel.

An average dose of the 1: 5000 dilution ofIsuprel for subcutaneous injection is 0.5 cc. Thisdose was assayed against intravenous histamineand methacholine (Figure 3). Weobtained com-plete (100 per cent) immediate protection againsthistamine and a continuation of significant levelsfor 30 minutes. Less anticholinergic effect wasnoted with this preparation, for the initial inten-sity was only 56 per cent, and it dropped to 40 percent in 18 minutes.

Sublingual tablets of Isuprel, although they havebeen moderately effective clinically in occasionalpatients, have not proved to be an adequate sub-stitute for a nebulizer in most cases. We haveperformed protection studies with these tabletsin doses of 20 mgm. (two tablets) against hista-mine and methacholine administered intrave-nously. Against histamine, significant levels ofprotection were not attained, and a peak of 38 percent was reached in 27 minutes. Against metha-choline the results were very similar although the40 per cent level was reached in 12 minutes afterthe tablets dissolved under the tongue. (Time fordissolution was usually two to three minutes.)The total duration of levels over 40 per cent was23 minutes. However, the peak level, attained24 minutes after dissolution of the tablets, wasonly 44 per cent. These data are presentedgraphically in Figure 3.

5. Ephedrine. From Table I it may be seenthat ephedrine is lacking in the hydroxyl groupson the benzene ring, and possesses an additionalmethyl group attached to the alpha-carbon atom.

Clinically it has longer, less intense action thanepinephrine; it is active orally.

In our studies, employing the usual oral doseof 25 mgm. (administered several hours after thesubject's last meal), there was a delay of 81 min-utes before a protection level of 40 per cent wasreached against histamine (Figure 4). A peaklevel of 57 per cent was attained at 120 minutes.Significant levels of 40 per cent or over weremaintained for 108 minutes, or until slightly overthree hours after the drug was taken. Againstmethacholine, no significant levels of protectionwere reached. The peak level was only 32 percent, occurring 60 minutes after ingestion of thetherapeutic agent.

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FIG. 4. THE PROTECTINGABILITY OF ORALLY ADMIN-ISTERED EPHEDRINESULFATE (25 MGM.) AND ORTHOXINE(200 MGM.) AGAINST HISTAMINE AND METHACHOLINE(REFERRED TO ABOVE AS MECHOLYL)

1187


6. Orthoxine.10 This synthetic amine differsfrom ephedrine in the absence of the beta-hydroxylgroup and the presence of a methoxy radical in theortho position.

Wehave made a clinical trial in approximately20 patients with a dose of 100-200 mgm. three tofour times daily. In general it proved to be oflittle benefit in preventing severe asthmatic at-tacks, although one patient obtained moderate re-lief and one noted marked improvement. Side-effects were observed by many patients and variedamong anorexia, nausea, light-headedness, dizzi-ness and drowsiness. Only one patient complainedof the ephedrine-like effect of insomnia. Thesyrup of orthoxine has been tolerated fairly welland appears to give clinical relief from troublesomecough in some patients.

In protection studies against intravenous hista-mine, orthoxine, in a dose of 200 mgm. orally,was apparently rapidly absorbed, for it displayed49 per cent protection at 57 minutes. In addition,this proved to be the peak level attained inasmuchas the protective capacity dropped very graduallyto 40 per cent at 165 minutes after ingestion ofthe drug. The total measured duration of signifi-cant protection was 108 minutes. Against metha-choline, a 40 per cent level was never reached.The peak attained was 38 per cent at 120 minutes.These figures for orthoxine, graphically presentedin Figure 4, obviously are very closely similar tothose for ephedrine.

SUMMARYAND CONCLUSIONS

1. Five well-known sympathomimetic aminesand one new one have been studied with respectto their protective capacity against the broncho-spastic effects of histamine and methacholine insensitive asthmatic patients.

2. No consistent difference in results was ob-served whether the bronchospastic agents wereadministered intravenously or as aerosols.

3. Epinephrine hydrochloride 1: 1000, 0.5 cc.subcutaneously, protected as well as or better thanthe other agents tested and afforded greater dura-tion of significant protection. However, its cardi-ovascular and central nervous stimulating side-reactions proved disagreeable.

10 Kindly supplied by The Upjohn Co., Kalamazoo,Michigan.

4. Isuprel 1: 100 aerosol (double the usualstrength), six inhalations, was comparable to thesubcutaneously administered epinephrine, particu-larly in anticholinergic effect, although it protectedless than half as long against histamine. This,too, caused undesirable side-effects.

5. Of the three most commonly employed solu-tions for nebulization, Vaponefrin, 2.25 per cent,appeared to have a slightly greater antihistaminicprotecting ability than Isuprel 1: 200 and epi-nephrine 1: 100. The latter two were of approxi-mately equal efficacy as antihistaminics. Isuprel1: 200 demonstrates greater anticholinergic pro-tecting ability than either of the other two prepa-rations.

6. Neosynephrin was quite ineffective when in-jected parenterally and of only slight value by theinhalatory route.

7. Sublingually administered Isuprel, in a doseof 20 mgm., proved to have little protective ca-pacity against the bronchospastic effects of hista-mine and methacholine. It was occasionally ofmoderate value clinically when administered bythis route.

8. Isuprel 1: 5000, 0.5 cc. subcutaneously, dis-played excellent though brief protecting abilityagainst the bronchospastic effects of histamine andconsiderably less effectiveness against metha-choline.

9. Isuprel 1: 50,000 could not, because of cardi-ovascular side-effects, be injected intravenouslyin doses sufficient to effect measurable protection.Doses of 0.25 cc. and 0.5 cc. (0.005 to 0.01 mgm.)occasionally proved dramatically effective in allevi-ating clinical asthma, although it usually was lesseffective and quite transiently so.

10. A new sympathomimetic amine, orthometh-oxy-beta-phenylisopropyl methylamine hydrochlo-ride (Orthoxine, Upjohn), of the class of ephed-rine, was studied and appeared quite similar to thelatter in protecting capacity. Brief clinical trialindicated that the ortho-methoxy group may oc-casionally reverse the central stimulation of ephed-rine.

ACKNOWLEDGMENT

We are indebted to Dr. H. J. Rubitsky for carryingout several protection study tests in this series.

1188


BIBLIOGRAPHY

1. Goodman, L., and Gilman, A., The PharmacologicalBasis of Therapeutics. The Macmillan Co., NewYork, 1941.

2. Barger, G., and Dale, H. H., Chemical structure andsympathomimetic action of amines. J. Physiol.,1910, 41, 19.

3'. Gunn, J. A., The pharmacological actions and thera-peutic uses of some compounds related to adrena-line. Brit. M. J., 1939, 2, 155.

4. Siegmund, 0. H., Granger, H. R., and Lands, A. M.,The bronchodilator action of compounds struc-turally related to epinephrine. J. Pharmacol. &Exper. Therap., 1947, 90, 254.

5. Lands, A. M., Nash, V. L., McCarthy, H. M.,Granger, H. R., and Dertinger, B. L., The pharma-cology of N-alkyl homologues of epinephrine. J.Pharmacol. & Exper. Therap., 1947, 90, 110.

6. Marsh, D. F., Pelletier, M. H., and Ross, C. A.,The comparative pharmacology of the N-alkyl-arterenols. J. Pharmacol. & Exper. Therap., 1948,92, 108.

7. Lands, A. M., Nash, V. L., Dertinger, B. L.,Granger, H. R., and McCarthy, H. M., Thepharmacology of compounds structurally related tohydroxytyramine. J. Pharmacol. & Exper. Therap.,1948, 92, 369.

8. Segal, M. S., Beakey, J. F., Bresnick, E., and Levin-son, L., Evaluation of therapeutic substances em-ployed for the relief of bronchospasm. Bull. NewEngland M. Center, 1948, 10, 21.

9. Levinson, L., Beakey, J. F., Bresnick, E., and Segal,M. S., Evaluation of therapeutic substances em-ployed for the relief of bronchospasm. II. His-torical development and methods. Ann. Allergy,1948, 6, 705.

10. Graeser, J. B., and Rowe, A. H., Inhalation of epi-nephrine for the relief of asthmatic symptoms.J. Allergy, 1935, 6, 415.

11. Richards, D. W., Jr., Barach, A. L., and Cromwell,H. A., Use of vaporized bronchodilator solutions inasthma and emphysema. A continuous inhalationmethod for severe asthmatic states. Am. J. M.Sc., 1940, 199, 225.

12. Segal, M. S., Beakey, J. F., Bresnick, E., and Levin-son, L., A comparison of various sympathomimeticamines in counteracting the dyspnea and broncho-spasm induced by histamine and acetyl-beta-methyl-choline. J. Allergy, 1949, 2G, 97.

13. Graeser, J. B., Inhalation therapy of bronchialasthma. J. A. M. A., 1939, 112, 1223.

14. Barach, A. L., Physiological methods in the diagnosisand treatment of asthma and emphysema. Ann.Int. Med., 1938, 12, 454.

15. Burrage, W. S., Recent therapeutic trends in allergy.New England J. Med., 1948, 238, 181.

16a. Konzett, H., Neue broncholytisch hochwirksameKbrper der Adrenalinreihe. Arch. f. exper. Path.u. Pharmakol., 1940, 197, 27.

b. Konzett, H., Zur Pharmakologie neuer adrenalin-verwandter K6rper. Ibid., 1940, 197, 41.

17. Segal, M. S., and Beakey, J. F., The use of isuprelfor the management of bronchial asthma. Bull.New England M. Center, 1947, 9, 62.

18.ISegal, M. S., and Beakey, J. F., Management ofbronchial asthma; the use of 1- (3',4'-dihydroxy-phenyl) -2-isopropylaminoethanol. Ann. Allergy,1947, 5, 317.

19. Cohen, E. N., and Van Bergen, F., Isuprel, a newbronchodilating agent. Bull. Univ. of Minn. Hos-pitals & Minn. Med. Foundation, 1948, 19, 424.

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Documents

EVALUATION 'OF THERAPEUTIC SUBSTANCES THE RELIEF OF€¦ · EVALUATION'OF THERAPEUTIC SUBSTANCES EMPLOYED FOR THERELIEFOFBRONCHOSPASM. V. ADRENERGICAGENTS By ELLIOTT BRESNICK,2 JOHN