Isoetharinewith PhenylephrineAerosol in Asthma

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1 J Clin Phrmcol. 1983; 23: Comprison of Fenoterol,Isoproterenol,od Isoethrineith PhenylephrineAerosol in Asthm GEORGE G. SPELLMAN, JR., M.D.,* BARBARA J. GRUEBEL, M.D., JOEL D. EPSTEIN, M.D., HAROLD H. ROTMAN, M.D., nd JOHN G. WEG, M.D. Ann Arbor, Mich. Abstrct: The bronchodiltor effect of fenoterol hydrobromide (.5, 1.25, nd 2.5 mg) s compred ith either isoproternol (2.8 mg) or isoethrine (5 mg) ith phenylephrine (1.25 mg) in double-blind plcebo-controlled study. When delivered by n intermittent positive-pressure brething device to 24 nonsmoking young dult sthmtic subjects, fenoterol produced significnt improvement in forced expirtory volume t 1 second (FEy1), in mximum midexpirtory flo (FEFn-75%), nd in forced expirtory flo t 25 per cent of vitl cpcity (FEF25%) for 6 to 8 hours, heres isoproterenol nd isoethrine ith phenylephrine produced improvement for 1 nd 2 hours, respectively. The loest dosge of fenoterol s s effective s the highest but hd feer dverse effects. F ENOTEROL hydrobromide, (1-3,5-dihydroxyphenyl)-1-hydroxy-2-(4-hydrox- yphenylisopropylmino)ethne (TH 1 165), structurlly relted to metproterenol, is reltively selective -drenergic gonist ith prolonged durtion of ction.15 The purpose of this study s to compre fenoterol in three different doses ith isoproterenol, isoethrine combined ith phenylephrine, nd plcebo, ll delivered ith n intermittent positive-pressure brething (IPPB) device to young dults ith uncomplicted Methods sthm. Tenty-four informed volunteer prticipnts (14 femle nd 1 mle) hd sthm chrcteried by episodic shortness of breth From the Pulmonry Division, Deprtment of Medicine, University of Michign Medicl School, Ann Arbor, Mich Supported in prt by grnt from Boehringer-Ingelheim, Ltd., Elmsford, N.Y. * Current ddress: 6699 Alvrdo Rod, Suite 238, Sn Diego, Clif nd heeing brought on by vrious stimuli hich chnged in severity spontneously nd ith therpy. They ere 18 to 3 yers old (verge 22 yers) nd hd hd sthm n verge of 17 yers (rnge 1 to 3 yers). Historiclly, 23 hd rections to identified llergens; 21 hd hyfever, ecem, ndor hives; nd 22 hd fmily members ith topic disorders. Of the 21 ho hd been skin tested, ll gve histories of positive immedite rections. Nineteen hd greter thn 5 per cent eosinophils in their peripherl blood. Tenty-one ere nonsmokers, hile three hd miniml pst smoking histories (.14 pck yers hving stopped three yers go,.12 pck yers hving stopped eight yers go, nd 3.8 pck yers hving stopped seven yers go). None hd chronic bronchitis or other respirtory diseses. In order to prticipte, the subjects hd to chieve 2 per cent improvement in their forced expirtory volume t 1 second (FEV1) 82 The Journl of Clinicl Phrmcology

2 FENOTEROL IN ASTHMA i I ILl -J C) cc L I C-) P._ - >- Ui I TIME (hrs. fter dmin.) Fig. 1. Per cent men chnge from bseline of FEy1 folloing dministrtion of plcebo (--F--); isoproterenol 2.8 mg (--I-); isoethrine 5 mg ith phenylephrine 1.25 mg ( IF ); fenoterol.5 mg (--FL--), 1.25 mg (-FM--), or 2.5 mg (-FH-). * Durtion for hich chnge from bseline of the tretment group is significntly greter thn the chnge from bseline of the plcebo group. ithin 3 minutes of receiving.15mg isoproterenol by metered dose inhler. They ere then excluded if their FEV1 s greter thn 7 per cent of predicted or if they hd crdic, renl, heptic, endocrine, or metbolic disese. Abnormlities of screening CBC ith differentil, blood sugr, BUN, SGOT, totl bilirubin, totl protein, lbumin, or electrocrdiogrm lso led to exclusion. Complete physicl exm nd history ere performed prior to study. The evlution s repeted t the completion of testing. Studies ere done the sme time ech dy but t lest 24 hours prt. No long-cting bronchodiltors ere tken for 12 hours, nd no other bronchodiltors or cromolyn sodium ere tken for 8 hours prior to or during testing. A stble dose of beclomethsone s continued throughout the study in three subjects, but otherise no ptient s receiving corticosteroids. Spirometry nd flo-volume loops ere done in triplicte to obtin the forced expirtory volume t 1 second (FEy1), forced vitl cpcity (FVC), mximum midexpirtory flo (FEFs-75%), nd forced expirtory flo t 25 per cent of vitl cpcity (FEF%). The mesurements from the test giving the best FEV1 ere used. On test dys, if the FEV1 s less thn 7 per cent of predicted, testing s continued nd spirometry, flo-volume loops, blood pressure, nd pulse mesurements ere done t bseline nd t 5 nd 3 minutes nd 1, 2, 3,4, 5, 6, nd 8 hours fter drug dministrtion. An Februry-Mrch

3 SPELLMAN, GRUEBEL, EPSTEIN, ETAL. electrocrdiogrm s tken t bseline nd t 3 minutes. Testing s discontinued prior to 8 hours if the subject s symptomtic nd the FEV1 hd returned to bseline. During the testing, the ptients ere specificlly questioned bout symptoms of nervousness, trembling, plpittion, vertigo, nd hedche. Ptients did quiet ctivities during the studies. Isotonic sline (plcebo), fenoterol hydrobromide (.5, 1.25, nd 2.5 mg), isoproterenol hydrochloride (2.8 mg), or combintion of isoethrine hydrochloride (5 mg) ith phenylephrine hydrochloride (1.25 mg) in norml sline s dministered in rndom order (tble of rndom numbers) ith the Port-Bird (Bird Corp., Plm Springs, Clif.) IPPB mchine using ir t setting of 15cm H2O. Niether the subjects nor the physicins dministering the pulmonry function tests kne the identity of the drug on test dy. Pulmonry functions ere performed ith rolling sel spirometer (Model 22), Pulmo-Norm Digitier (Model 56), nd n X-Y recorder (Model 75) produced by Crdio-Pulmonry Instruments Corp., Houston, Tex. Sttisticl nlysis of results s crried out ith comprison beteen pired vribles mde ith the t-test (significnce level.5) nd multiple comprisons mong vr- 16 -J Ui 144 C,) I P. J Lii 96 8O Z 64 Lii 48 P p,---.., #{149}..I. *,,.. EM P p32- It) U 6 I TIME(hrs. fter dmin.) Fig. 2. Per cent men chnge from bseline of FEFj-m* folloing dministrtion of plcebo (--F--); isoproterenol 2.8 mg ( -I- ); isoethrine 5 mg ith phenylephrine 1.25 mg ( IP#{149} ); fenoterol.5 mg (--FL--), 1.25 mg (-FM-) or 2.5mg (-FH-). * Durtion for hich chnge from bseline of the tretment group is significntly greter thn the chnge from bseline of the plcebo group. 84 The Journl of Clinicl Phrmcology

4 FENOTEROL IN ASTHMA l II * 48 #{176} 32 I ) cj LU P I I I I I I I I TIME(hrs. fter dmin.) Fig. 3. Per cent men chnge from bseline of FEF.25, folloing dministrtion of plcebo (--P--); isoproterenol 2.8 mg isoethrine 1.25 mg (#{149}IP); fenoterol.5 mg (--FL--), 1.25 mg (-FM-), or 2.5 mg (-FH-). * Durtion for hich chnge from bseline of the tretment group is significntly greter thn the chnge from bseline of the plcebo group. ibles mde ith Duncn s multiple rnge test (significnce level.5). The study design s pproved by the Committee to Revie Grnts for Clinicl Reserch nd Investigtion Involving Humn Beings of the University of Michign Medicl School. Further informtion from the Food nd Drug Administrtion relting to the incresed incidence of tumors in rts receiving lbuterol s given to the prticipnts hen it becme vilble during the study, nd those ho hd not completed the study ere required to give this dditionl consent before continuing. Results Testing s discontinued in 2 instnces (four ith plcebo, four ith isoethrine ith phenylephrine, three ith isoproterenol, nd to ith ech dose of fenoterol) becuse the subjects ere symptomtic nd the FEy1 hd returned to bseline. There s no significnt difference in bseline FEy1, FEF25-75, nd FEF25c, mong tretment groups. Percentge men chnges in FEy1, FEF25-m, nd FEF2, re shon in Figs. ito 3, nd Tble I. Fenoterol hd longer durtion of ction thn either isoproterenol or isoethrine ith phenylephrifle. The men chnges from bselines in FEy1 nd FEF25, of the three fenoterol tretment groups ere not different t 8 hours. The men chnges from bselines in FEF25-75, of the three fenoterol tretment groups ere not different t 6 hours. But t 8 hours, the men chnge in FEF-m;, s greter for the 2.5-mg fenoterol tretment group thn for the 1.25-mg fenoterol tret- Februry-Mrch

5 Ii o SPELLMAN, GRUEBEL, EPSTEIN, ETAL. ment group, hile the.5-mg fenoterol tretment group s not different from either the 2.5-mg or the 1.25-mg fenoterol. tretment group., NmiODinQOC - N C - o c i There s no significnt chnge in blood b* E ooi pressure during testing. The men systolic C blood pressures rnged beteen nd. o mm Hg, nd the men distolic blood pressures rnged beteen 68.6 nd 76.8 mm Hg. Invribly, the men pulse rte decresed in 1 1 C ith tretment, but the chnges from bse- 6 ci ci ci ci ci ci ci ci line ere not significnt. The men pulse - rnged beteen 78.7 nd 94.3 betsmm. The pulse rte incresed nd s greter thn 1 betsmm folloing tretment in four cses ith plcebo (highest 12 bets o - CC CC N CC ci N mm), in to cses ith isoethrine ith o in in phenylephrine (highest 136 betsmm), in - mincon-ccc b six cses ith isoproterenol (highest 132 In betsmm), in four cses ith.5 mg fenoci terol (highest 126 betsmm), in to cses o ith 1.25 mg fenoterol (highest 12 bets - Il mm), nd in three cses ith 2.5 mg feno C- CO in - terol (highest 12 betsmm). With the cx-. o co CC o C- ception of sinus tchycrdi, the electro- - CC N 4 1 CC C1 C4. coicoin.e.coco.- ci ci ci ci ci ci ci ci crdiogrms ere norml. Tble II summries the dverse experience ith ech tretment. The blood sugr, BUN, SGOT, totl bilirubin, totl protein, lbumin, nd urinlysis ere CCCOCCCcC norml t the beginning nd end of testing,, N1N N CO C CC 4 N CC N N CC in s s the CBC ith differentil, ith the C C O N CC CC in - CO ci cq 1 1 ci 1 ci exception of the incresed eosinophil count in 19 subjects. Discussion CC Fenoterol in studies ith plcebo con trols hs previously been found to be effec- N CC 1 CO CO tive not only hen delivered by msk to symptomtic sthmtic children studied for 1 hour, but lso hen delivered by metered dose inhler to sthmtic dults ith unspecified smoking histories studied for 8 hours.3 To studies ith plcebo con-.6 trols found fenoterol to hve significnt 8 in CO CI CO in CC CC nd prolonged bronchodiltor effects hen dministered orlly to six ptients ith 86 The Journl of Clinicl Phrmcology

6 FENOTEROL IN ASTHMA I.1 CC CO,-1 CC CO 4 be 8 In. be 8 In ci - 4 N 4 be 8 in ci -.- O Wi -o - E. 4 in o 4 4 CO - - s, - -I I1. CC in CO CC CC --. C) CO be C). - o. x....i eqs be. n 8 o.r o Z oe E-D.,..OE- I1XZ Februry-Mrch

7 SPELLMAN, GRUEBEL, EPSTEIN, ETAL. bronchil sthm nd four ith sthmtic bronchitis ith or ithout emphysem,2 nd hen dministered orlly to five ptients ith sthm nd 15 ptients ith combintions of sthm, bronchitis, nd or emphysem ith unspecified smoking histories.4 In the present study, fenoterol, hen dministered ith n intermittent positivepressure brething device to nonsmoking young dult sthmtic subjects, produced significnt improvement in expirtory flos t ech lung volume s mesured by FEV,, FEF25-?s% nd FEF25% for 6 to 8 hours s shon in Figs. 1,2, nd 3. When compred to plcebo, the highest fenoterol dose (2.5 mg) hd longer effect on FEV, nd FEF-7s thn the loest fenoterol dose (.5 mg); but hen both fenoterol doses ere compred to ech other, there s no difference. The durtion of ction of fenoterol s superior to both isoethrine ith phenylephrime (2 hours) nd isoproterenol (1 hour). Previous studies hve not investigted the effect offenoterol on expirtory flos t lo lung volumes. Figure 3 shos tht fenoterol produces prolonged improvement in the forced expirtory flo t 25 per cent of vitl cpcity. The importnce of plcebo controls is indicted by the improvement noted in the plcebo tretment group in this study nd others. 34 In ddition to the plcebo effect, prt of the improvement is probbly relted to the nturl tendency tord improvement during the first keful hours5 nd the subsequent reltively quiet test period. The experimentl design of discontinuing testing in symptomtic subjects hose FEy1 hd returned to bseline exggertes plcebo group improvement. Adverse effects of tretment ere lest frequent ith.5 mg fenoterol; intermedite in frequency ith 1.25 mg fenoterol, isoethrine ith phenylephrine, nd isoproterenol; nd most frequent ith 2.5 mg fenoterol (Tble II). Fenoterol hs thus been found to be n effective bronchodiltor for tretment of sthm in young dult nonsmokers hen delivered by IPPB ith durtion of ction of 6 to 8 hours. It hs been shon to improve ir flos t lo lung volumes. Incresing the dosge of fenoterol from.5 mg to 2.5 mg produced more side effects but did not improve bronchodiltor ctivity. References 1. Blckhll MI, Duth M, Mhoney M, O Donnell SR. Inhltion of fenoterol (Berotec) by sthmtic children. Med JAust. 1976; 2: Gemei AM, Miller WF, Miller J, Gst, LR. Bronchodiltor effect of ne orl bet drenergic stimulnt, TH Chest. 1976; 7: Pennock BE, Rogers RM, Ryn BR, Ayers LN. Aerosol dministrtion of fenoterol hydrobromide (Th 1 165) in subjects ith reversible obstructive iry disese. Chest. 1977; 72: Steen SN, Smith R, Kuo J, Ziment I, Bell G. Comprison of bronchodiltor effects of orl therpy ith fenoterol hydrobromide nd ephedrine. Chest. 1977; 72: Soutr CA, Costello J, Ijduol, Turner-Wridk M. Nocturnl nd morning sthm; reltionship to plsm corticosteroids nd response to corticl infusion. Thorx. 1975; 3: Reprint requests to: Dr. John G. Weg, Pulmonry Division, Box 55, University Hospitl, S1136, Ann Arbor, Mich The Journl of Clinicl Phrmcology