The effect of metaproterenol in chronic asthmatic children receiving therapeutic doses of theophylline

he effect of metaproterenol in chronic sthmatic children receiving therapeutic oses of theophylline Stanley P. Galant, M.D., Charles E. Groncy, arvalakshmi Duriseti, M.D., and Lawrence h-vine and Tujunga,

M.D., Strick, M.D.

Calif.

The effect of metaproterenol added to therapeutic doses of theophylline was compared with a combination of placebo and theophylline by measurement of the forced expiratory volume in I set (FEV,), forced vital capacity (FVC), and maximum midexpiratory Jlaw rate (MMEFR) in 17 asthmatic children in a double-blind crossover study. Plasma theophylline levels were measured at 1.5 hr (peak) and 6 hr (trough) after drug administration on all test days. Children weighing less than 60 pounds received 10 mg of metaproterenol(1 tsp), while those weighing more than 60 pounds received 20 mg every 6 hr. The mean peak theophylline level for both metaproterenol and placebo treatment days was approximately IO pgiml, while the trough was 6 pglml. Metaproterenol caused a significantly greater increase in FEVI (p < 0.05) of 17% at 1.5 hr when given with theophylline than the placebo-theophylline combination. The metaproterenol effect on MMEFR was even greater with increases over placebo of more than 80% at I.5 hr and 2 hr (p < 0.0025) and 30% at 3 hr and 4 hr (p < 0.05). No increase in adverse effects with the metaproterenol-theophylline combination compared with placebo-theophylline was observed. This study suggests that metaproterenol can improve pulmonary function of both large and small airways when added to moderate theophylline doses without risking increased side effects in asthmatic children.

The pharmacologic approach to bronchial asthma has emphasized the importance of increasing intracellular cyclic 3’5’ adenosine monophosphate (cyclic AMP) in the bronchial smooth muscle and lung mast cell. This can be achieved in two ways: beta adrenergic stimulation with activation of adenyl cyclase which converts adenosine triphosphate (ATP) to cyclic AMP and phosphodiesterase inhibition by the methylxanthine, theophylline, which prevents the degradation of cyclic AMP to the inactive 5’-AMP.r A recent resurgence of interest in theophylline pharmacology has demonstrated the clinical usefulness of theophylline in treating bronchial asthma.2s 3 However, the narrow margin between therapeutic and toxic dosage limits its usefulness somewhat, especially when serum theophylline levels cannot be

closely monitored. Since theophylline and beta adrenergic stimulants have been shown in vitro to interact synergistically in inhibiting allergic histamine release from human leukocytes,* it would seem that a combination of the two types of drugs would be chnitally useful. Weinberger and Bronskyj found that a high dose of theophylline was of equal eFficacy and had fewer side effects than a fixed combination of high-dosage theophylline and ephedrine. However, ephedrine is a relatively weak bronchodilator and has potentially undesirable alpha and beta- 4 adrenergic side effects. Metaproterenol is a superior bronchodilator and is predominantly a beta adrenergic agonist with some beta-2 selectivity.6 Studies involving aerosol administration of metaproterenol to asthmatic children indicated greater improvement in pulmonary function, longer duration of action, less tachycardia, and increased pulse pressure than with isoproterenoL7 A recent study has demonstrated the safety and efficacy of metaproterenol given orally to asthmatic children over a 3-mo period.8 The purpose of this study was to compare both the therapeutic and potentially adverse side effects of metaproterenol combined with therapeutic doses of

Prom the Department of Pediatrics, University of California, Irvine, and Sunair Home for Asthmatic Children. Supported by a grant from Boehringer Ingelbeim (New York Ltd.). Received for publication June 20, 1977. Accepted for publication Oct. 20, 1977. Reprint requests to: Stanley P. Galant, M.D., Department of Pediatrics, University of California Irvine Medical Center, 101 City Drive South, Orange, Calif. 92668. OOSI-6749/78/0261-0073$00.70/O

0

1978

The

C. V. Mosby

Co.

Vol.

61, No.

2, pp. 73-79

4

Gaiant

J. ALLERGY CLIN. IMMUNOL. FEBRUARY 1978

et al.

Theophylline 0 +Metoproterenol

TIME

FIG. I. The percentage increase the metaproterenol-theophylline with the placebo-theophylline test period.

theophylline alone when

(hours)

in FEV, above baseline of combination compared combination over the 6-hr

with those resulting from theophylline given to children with chronic asthma.

TH

tient

population

The study group population included asthmatic children who were residents at the Sunair Residential Hospital in Tujunga, California. The age range was from 7 to 14 yr (mean, 9.7 yrs); there were 12 boys and 5 girls. Almost all were atopic by history and skin testing. All had previously demonstrated (within 3 mo of the study) at least a 20% increase in FEV, following inhalation of isoproterenol. All were receiving maintenance, around-the-clock theophylline sufficient to give a peak serum tbeophylline level greater than 10 pg/ml at the time of entry into the study. This was determined by high-pressure liquid chromatography analysis.

xpe~~me~tai

design

The experimental design used was the double-blind crossover method. On each testing day, the patient had to have a FEV, of no more than 75% of predicted normal values for height and sex.s Since many patients had values greater than 75% of predicted when they had received theophylline 6 hr before, no medication was allowed for 12 hr before beginning the testing for the day. Each subject then received his/her previously determined oral dose of theophylline and the test drug, either metaproterenol or placebo, chosen in a randomly determined, double-blind manner. The metaproterenol dose for children weighing less than 60 pounds was 10 mg (1 tsp) and that for those weighing more than 60 pounds was 20 mg (2 tsp). Spirometric measurments consisted of a forced expiratory volume in I set (FEV,), forced vital capacity (FVC), and maximum midexpiratory flow rate (MMEFR) with the use of a Jones Pulmonar. The best response obtained from three attempts at each test hour was recorded. In addition, blood pressure, pulse, respiratory rate, and all adverse effects

were recorded both before the drugs were taken at baseline and also at 1.5, 2, 3, 4, 5, and 6 hr after the drugs were given. Serum theophylline levels were obtained at 1.5 and 6 hr. After the 6-hr testing period, patients continued the same treatment regimen on metaproterenol or placebo in addition to theophylline for 3 days, taking the medications orally every 6 hr in order to evaluate the effect of drug loading and possible tachyphylaxis. A diary was kept by the nursing personnel to note the times of medications, symptoms, and side effects. On the third day of this regimen, the same testing procedure as on day 1 was performed (second test day). After this second test day, a 24-hr washout was allowed before the patients crossed over to the other test drug (metaproterenol or placebo), and the above procedure was repeated. Patients who received metaproterenol first, then placebo, were designated as group I, while those with the opposite sequence of placebo-metaproterenol were designated as group II. At the completion of each 3-day treatment period, the investigator and each patient evaluated the response to the drug regimen as excellent, good, fair, no change, or worse. At the end of the study, the investigator and each patient compared the two treatment periods and stated a preference. No other investigational drugs were allowed during the course of the study. Steroids were allowed if the patient was maintained on a dosage of no more than 10 mg prednisone daily or 20 mg every other day or an equivalent of Vanceril (400 ,ug/day). This dosage was not varied throughout the study. Moreover, no cromolyn sodium or combination bronchodilators with ephedrine and theophylline were allowed throughout the study. Data were analyzed by means of the analysis of variance and student test methods. The theophylline preparation used was aminophylline tablets (United States Pharmacopeia) in all cases.

RESULTS Pulmonary

function

tests

The mean and standard deviation for the baseline and postdrug values for test days 1 and 2 and drug sequence group I (metaproterenol-placebo) and group II (opposite sequence) were compared. No statistically significant differences between test days or drug sequence were found. Therefore, the data are reported combining the two test days in group I and group II for each test drug. The effect of metaproterenol on the FEV, is seen in Table I and Fig. 1. The mean baseline FEVl values for metaproterenol (1,100 ml) and placebo (1,059 ml) were very comparable. There was a small (17%) but statistically significant (p < 0.05) difference in percentage increase of the FEVr over the baseline with the metaproterenol-theophylline combination compared with the placebo-theophylline combination at 1.5 hr. At 2 hr, the mean difference between metaproterenol and placebo of 15% did not reach statistical significance (p > 0.05 < 0.1). The number of patients showing greater response to metaproterenol than placebo was 12 of 17 at 1 hr and 9 of 17 at 2 hrs (Table I). The effect of metaproterenol on the MMEFR, seen in Table II and Fig. 2, was much more profound than the effect

VOLUME 61 NUMBER 2

Metaproterenol aseline FEV, values (P), and the percentage

P

placebo

of each patient, the group mean before metaproterenoi increase over baseline for the 6-hr evaluation period % increase

Subject

Drug

Baseline FEV, (ml)

1.5 hr

1

M P M P M P M P M P M P M P M P M P M P M P M P M P M P M P M P M P

6.50 775 700 600 1,450 1,100 1,225 1,400 1,200 950 500 700 1,075 1,150 1,600 1,500 1,275 900 1,350 1,040 1,325 1,350 850 900 1,050 1,100 950 956 1,300 1,787 1,116 800 1,100 1,000

169 68 86 25 31 46 35 25 71 53 60 43 16 39 38 7 14 44 37 73 66 26 27 6 33 14 26 73 77 6 61 44 46 10

192 36 89 35 21 46 31 14 88 58 80 36 30 30 25 33 10 78 33 78 59 33 41 33 43 18 16 52 77 9 34 94 36 40

M P

1,100 1,059

52* 35

58 43

2 3

4 5 6 7 8 9 9 13 II 12 13 14 15 16 17

Mean

and t~e~~h~~~~n~

2 hr

over

3 hr

107 81 64 38 15 55 31 20 83 61 80 50 30 39 19 15 2 78 33 73 57 52 47 33 14 -13 24 39 62 9 48 88 25 5.5 44 46

7%

(

baseline

4 hr

103 74 79 50 29 43 10 36 58 58 85 18 44 -11 -6 -6 29 105 33 71 56 5.5 19 36 28 11 29 41 73 17 12 12 27 10

92 42 45 42 22 59 18 -2 38 47 15 32 40 22 -13 31 29 89 37 54 77 37 18 40 5 0 11 46 62 23 3 6 18 -20

77 27 36 50 I 36 16 -11 56 37 70 29 35 7 3 22 2 97 33 67 32 55 41 21 7 7 -32 24 54 -44 3 -25 55 23

42 37

30 32

29 25

rStatisticai significance, p < 0.05. on FEV,. The mean baseline values for metaproterenol (0.85 L/see) and placebo (0.79 L/set) were again quite comparable. The metaproterenol-theophylline combination showed a highly statistically significant (p < 0.0025) difference in percentage increase of MMEFR above baseline compared with the placebo for 1.5 and 2 hr and remained statistically significant (p < 0.05) for 4 hr after drug administration. In Table II, one sees a greater response in the metaproterenol combination at 14 of 17 patients at 1.5 hr, 12 of 17 at 2 hr, and 11 of 17 patients at 3 and 4 hr. Although there was considerable variability at 6 hr, there appeared to be some metaproterenol effect even at that time. Thus, 59% of the patients showed a better FEV’response

with the metaproterenol-theophylline combination compared with the placebo combination and 76% showed a better MMEFR response with the metaproterenoltheophylline combination at 6 hr after drug administration. Any differences for FVC between metaproterenol and placebo treatment were not statistically significant.

Plasma-theophylline

levels (

There were no significant differences in mean peak (1.5 hr) or trough (6 hr) plasma-theophylline levels between the metaproterenol (10.66 f 3.38 pg/mI and 6.24 +- 2.58 pg/ml, respectively) and placebo (11.24 I: 3.46 ,ug/ml and 6.58 k 1.98 pg/ml, respectively) treatment days. Further-

J. ALLERGY CLIN. IMkNJMOL. FEBRUARY 1978

7% Gaiant et al.

FIG.2. The percentage increase in as explained

in the

legend

for

Fig.

MMEFR 1.

more, there were no significant differences days 1 and 2 or patient groups I and II.

above

baseline

between test

No significant overall changes in heart and respiratory rate or systolic or diastolic blood pressure occurred with either the metaproterenol-theophylline combination or the placebo-theophyliine combination when compared with baseline values.

There were few side effects reported in either treatment group. Two patients receiving metaproterenol reported adverse effects: One had a headache and the other mild jitteriness. The latter patient reported moderate jitteriness while receiving the placebo.

verall evaluation No subjective improvement from the patients’ usual clinical status on either drug regimen was noted by either physician or patient during the 3-day maintenance period. Moreover, no preference for either metaproterenol or the placebo was expressed.

ISCUSSION The methylxanthine, theophylline, is currently considered the major bronchodilator drug in the therapy of bronchial asthma. Weinberger and Bronsky5 have shown that high-dose theophylline therapy with peak theophylline levels above 10 pg/ml gives as good control of asthma, measured by symptom and medication score and pulmonary function, as a fixedratio combination of high-dose theophylline and

ephedrine. In fact, the addition of ephedrine was associated with a greater incidence of side effects than theophylline alone. Neither low-dose conventional therapy of theophylline and ephedrine (in fixed combination) nor high doses of ephedrine alone differed significantly from the placebo in controlling the asthma in these chronic asthmatic children The mean peak serum theophylline level achieved with low-dose therapy was 6.5 pg/ml, compared with 13.0 pglml with high-dose therapy. The 5: 1 theophylline-toephedrine ratio in the latter combination resulted in a mean ephedrine dose of 1.25 mg/kg per dose. It is no small wonder that increased side effects were noted. In contrast to the findings of Weinberger and Bronsky, two studies have suggested an additive effect of ephedrine on theophylline in improving pulmonary function. Taylor and co-workerslO showed in a short-term study that both ephedrine (1 mg/kg/dose) and theophylline (5 mg/kg) resulted in significant bronchodilation as measured by peak expiratory flow rate (PEFR) and FEV, with a peak response at 2 hr after drug administration. The addition of ephedrine and theophylline gave a small additive effect which was not, however, statistically significant. No serum theophylline levels were measured, but only 20% of the children would be expected to exceed 10 kg/ml with a theophylline dosage of 5 mgikg.l’ In a more recent paper, Tinkelman and Avner12 showed that ephedrine (mean dose, 0.84 mg/kg) given 2 hr after high-dosage theophylline therapy (previously shown to give peak theophylline > 10 pglml) caused a small but significant increase in peak expiratory flow rate (PEFR) and FEVl compared with the theophylline baseline. However, no direct comparison is made between the ephedrine and placebo effect on pulmonary function. Such a comparison is really necessary since the placebo value reflects the true theophylline baseline. Over an g-wk period, there were no increased side effects in those treated with ephedrine and theophylline over those in the group treated with theophylline alone. It would have been helpful to have monitored the serum theophylline level during the short-term study to have better defined the interaction of ephedrine and theophylline. However, this study strongly suggests that the patient receiving therapeutic doses of theophylline may achieve additional bronchodilation from a sympathomimetic agent without necessarily risking increased side effects. Our study is an extension of this concept. We have used metaproterenol, an agent that is a more potent bronchodilator than ephedrine and exerts less alpha and beta- 1 stimulation-characteristics that give many of the side effects noted with ephedrine. The

% increase

over

baseline

Baseline MMEFR (Llsec)

16

M P

17

M P

0.28 0.37 3.11 0.34 1.04 0.60 1.27 1.38 0.86 0.58 0.34 0.33 0.74 0.69 0.64 0.71 0.75 0.91 1.06 1.56 0.77 0.76 0.38 0.62 0.76 0.98 0.74 0.82 0.65 I .56 0.59 0.50 0.53 0.69

Mean

M P

0.85 0.79

1 2

3 4 5 6 7 8 9 10 11 12 13 14 15

M

P M P M P M P M P M P M P M P M P M P M P

M IP &!I !P M IP M 1’

259 34 37 12 185 120 90 18 87 91 47 158 112 45 254 19 61

310 26 40

228 70 -74

11

io

169 -51 166 36 85 -8 53 63 61 34 257 4 82 49 60 0

33 128 156 13 134 72 224 67 39 36 270 27 39 5 72 83 134 68 108 13 18 16 49 142 256 -5 57 31 190 30

179 208 18 16 122 83 144 130 73 46 144 47 10 51 159 178 131 98 84 0 6 -46 102 83 179 6 124 43 2 49

193 114 72 34 64 108 30 67 120 72 129 39 12 37 101 38 28 50 126 37 88 92 100 37 22 -6 1 86 287 -7 95 -7 43 10

121” 37

129” 45

96’i 63

89$ 47

110

48 -77 16 119 113 13 -91 11 72 32 24 32 -27 64 25 -6 158 126

15 68 52 33 10 -10

-15 26 111 145 -35 -13 5 52 58 43 37

85 18 -81

43 44 18

-13 -27 73 58 241 -2 -3 -10 IS9 10 -35 21 88 66 45 55 156 21 -2: -21 -40 89 120 -51 -11

-36 98 58 60 18

“p < 0.0025. 0.025. $p < 0.05.

ip <

metaproterenol effect was evaluated at presumably the height of the serum theophylline level, 1.5 hr after drug administration and for 4.5 hr following this point (6 hr after drug). Unlike the study of Tinkelman and Avner, the action of the sympathomimetic agent was evaluated Pnthe presence of a known serum theophylhne level. The combination of metaproterenol and resulted in a small (17%) but theophylline significantly (p < 0.05) greater increase in the FEVl than the theophylline and the placebo at 1.5 hr. At 2 hr, the metaproterenol combination was 15% greater than the placebo combination; but because of varia-

bility of response, this did not reach statistical significance (p > 0.05 < 0.1). The effect of metaproterenol was more striking on the MMEFR, which is thought to reflect small airway function.r3 It was more than 80% greater than placebo for the first 2 hr (p < 0.0025) and over 30% greater for the third (p < 0.025) and fourth hours after drug (p < 0.05) (Fig. 2). The response of our study population was fairly uniform with parallel improvement frequently noted in both FEV, and MMEFR measurements. Significant improvement in MMEFR was noted to occur even after the FEVl had returned to a normal

J. ALLERGY CLIN, IM~~~OL. FEBRLiARY 1975

TA 111.Mean and 1 SD plasma theophylline levels at peak (1.5) hr and trough metaproterenol or placebo in combination with theophylline Metaproterenol roup

Group I (9) Day I Day

2

Group II (8) Day I Day 2 Mean

(6 hr) times

after

Placebo

1.5 hr

6 hr

1.5 hr

6 hr

IO. 10

6.90 7.30

12.60 12.40

6.90 6.40

4.80 5.70

9.00

10.40

6.20 6.80

11.90 8.90

11.70 10.66 + 3.38

6.24

+

11.24 + 3.46

2.58

6.58 + 1.98

Group I patients received metaproterenol first, placebo second; group II had the opposite sequence.

range which suggests the MMEFR was reflecting changes in small airway function. Previous studies on sympatho~metic-theophylline combination therapy5* 7* ’ have not emp hasized the effect on small airways. It could be argued that the effect of metaproterenol was dependent on the serum theophylline level. Thus, metaproterenol should have a more profound effect -when the theophylline level was low and a decreased effect with higher theophylline levels. Our study was not designed to compare the effect of metaproterenol on high and low theophylline levels. Certainly, the differences noted between metaproterenol and the placebo could not be explained on this basis since there were no significant differences in theophylline levels between the two (Table III). The mean peak theophylline level of 10 pug/ml in this study was at the low end of the therapeutic spectrum (10 to 20 pg/ml). However, as suggested by Figs. 1 and 2, we cannot exclude the possibility that the peak theophylline level w-as reached at 2 hr, as opposed to 1.5 hr with aminophylline tablets, and could therefore have been higher than we reported. Actually, the mean peak theophylline level in our patients was greater before the study, with all patients having peak levels above 10 p.g/ml. However, to standardize the baseline (FEV, s 75% predicted) for all test days, all medication was withheld for 12 hr before drug administration instead of the usual 6-hr dosing interval since there appears to be an inverse relationship between the baseline value and bronchodilator response.14 At 6 hr after theophylline, most of the patients had had FEV, values above 75% predicted, thus necessitating the B2-hr requirement. The median theophylline dose required to give children (5 13 yr) a theophylline level of 10 pg/mI is approximately 6 mg/kg every 6 hr.‘l Our study suggest that with this theophylline dosage, the sympathomimetic agent metaproterenol causes significant improvement in large and small airway

function. Furthermore, given in this combination, there was no potentiation of cardiovascular of neurologic side effects. Finally, there was no indication that a loading period was necessary for maximal metaproterenol effect, nor was there evidence of tachyphylaxis after the short period of daily administration of metaproterenol in this study. Our study does not answer the question of whether or not the newer, more potent and selective beta-2 adrenergic agents would improve pulmonary function in those patients receiving high-dosage theop~ylli~e. However, since the therapeutic index for theopb~lline is rather narrow and theophylline kinetics are extremely variable among asthmatic children,*5 high-dose theophylline therapy requires the facility to accurately measure serum theophylline levels. In situations in which this is not possible, the physician can improve the patient’s pulmonary function by adding metaproterenol to moderately high doses of theophylline (5 to 6 mg/kg) without the risk of increasing side effects. We thank Pat Prichard for preparation of the manuscript, Betty Rawlings for editing, and John Orcutt for performance of plasma theophylline levels. REFERENCES Middleton,

E.,

Jr.:

Autonomic

imbalance

in asthma,

with

special reference to beta adrenergic blockade, Adv. Intern. Med. 19:177, 1973.

d.

Mitenko, P. A., and Qgilvie, R. I.: Rational intravenous doses of theophylline, N. Engl. J. Med. 289600, 1973. Weinberger, M. M., and Riegelman, S.: Rational use of theophylline for bronchodilation, N. Engl. 5. Med. 291: 151, 1974. Lichtenstein, L. M., and Margolis, S,: Histamine release in vitro: Inhibition by catecholamines and metbylxanthines, Science 161:902, 1968. Weinberger, M. M., and Bronsky, E. A.: Evaiuation of oral bronchodilator therapy in asthmatic children, J. Pediatr. 84:421, 1974.

6. Campbell, A. B., and Soyka, L. F.: Selective beta2receptor agonists for the treatment of asthma-therapeutic breakthrough or advertising ploy? J. Pediatr. 89~1020, 1976. 7. Hurst, A.: Metaproterenol, a potent and safe bronchodilator, Ann. Allergy 31:460, 1973. 8. Brandon, M. L.: Long-term metaproterenol therapy in asthmatic cbildmn, J. A. M. A. 235:736, 1976. 9. Koptezky, M. T., Maselli, R., and Ellis, E. F.: Pulmonary function studies with simple equipment in 323 normal children, .I. ALLERGY CLIN. IMMUNOL. 53:1, 1974. 10. Taylor, W. F., Heimlich, E. M., Strick L., and Busser R.: Ephedrine and theophylline in asthmatic children: Quantitative observations on the combination and ephedrine tachyphylaxis, Ann. Allergy 23:437, 1965. 11. Weinberger, M. M., and Ginchansky, E.: Theophyllinization of the child with chronic asthma, in Proceedings of the Inter-

national Symposium on Clinical Pharmacy and Clinical Pharmacology, New York, Excerpta Medica Foundation. (In press.) 12. Tinkelman, D. G., and .4vner, S. E.: Ephedrine therapy in asthmatic children. Clinical tolerance and absence of side effects, J. A. M. A. 237:553, 1977. !3. Souhrada, J. F., and Buckley, J. M.: Pulmonary function tcsting in asthmatic children, Pediatr. Clin. North Am. 2.3~249, 1976. 14. Tinkelman, D. G., Avncr, S. E., and Cooper, D. M.: Assessing bronchodilator responsiveness, J. ALLERGY CLIN. IMMU~V~L.

59:109,

1977.

15. Ellis, E. F., Koysooko, R., and Levy, G.: Pbarmacokinetics theophylline in children with asthma, Pediatrics. 5 1976.

of