Ambulatory long-term subcutaneous salbutamol infusion in chronic severe asthma

Ambulatory salbutamol

long-term subcutaneous infusion in chronic severe asthma

M. Clutel, MD,* J. Bousquet, MD, PhD,* J. P. Daures, MD, PhD,** D. Renon, MD,*** A. M. Clauzel, MD,* P. H. Godard, MD,* and F. B. Michel, MD’ Montpellier and Paris. France Although most patients with asthma improve with currently available drugs. there appears to lx, a subset of patients with asthma resistant to intensive treatment, including large doses o/ systemic corticosteroids. In IO patients with asthma d@cult to treat. a double-blind, placebo-controlled, crossover study was performed to evaluate whether long-term. continuous subcutaneous infusion of large doses of salbutamol. in addition to steroids. could improve pulmonar?, junction, compared with intermittent nebulization ojsalbutamol. Four weeks I?/ administration of large doses (>I4 mglday) of &-agonists were well tolerated, elicited u significant decrease ojcorticosteroid consumption (p < 0.01). and were associated with an improvement in pulmonary function (p < 0.01). compared with run in or the placebo administration period. Mean morning and evening peak e.rpiratory flow rates were similar during all periods, and the variability between morning and evening peak expiratory jlow rate.) was onlv slightlv and nonsignificantly reduced during the period when salbutamol was administered subcutuneously. Both nebulized and subcutaneous .salbutamol elicited similar metabolic and muscular side effects, but these untoward reactions never caused any patient to stop the treatment. L.ocal injection at the injection site wus observed in two of 10 patients with continuous subcutaneous infusion. Tachyphylaxis to &-agonist. as measured by the reversihilic oj FEV, to inhaled salbutamol 12 hours after the end of each period, did not occur. In conclusion. large doses of &-agonist administered to putients with severe. chronic, and steroid-dependent asthma were able to improve respiratory function and to decrease corticosteroids requirements. (J ALLERGY CLN IMMJ.VOI. I Y90:85:599-605. I

Asthma is a complex disease, although most patients have improved with currently available drugs. There appears to be a subset of patients with asthma either resistant to usual treatment, including large doses of systemic corticosteroids’-3 or having brittle asthma.’ ’ Some investigators proposed treating these patients with depot preparations of corticosteroids,6.7 but this treatment is not always effective and often induces severe systemic side effects. Beta,-agonists were initially administered by oral route and in the form of MDIs.‘-‘~ Many studies have demonstrated greater efficacy for the treatment of severe asthma exacerbation when &agonists were ad-

From the Winique des Maladies respiratoires and **D+artement d’informatique mtiicale, Centre Hospitalier Universitaire. Montpellier, and ***Glaxo France, Paris, France. Received for publication May 30, 1989. Revised Oct. 18. 1989. Accepted for publication Oct. 18, 1989. Reprint requests: Marc Cluzel. MD, The Johns Hopkins Asthma and Allergy Center, Clinical Immunology Office 7. 301 Bayview Blvd., Baltimore. MD 21224.

l/1/17558

Abbreviations used

PEFR: Peakexpiratory flow rate MDI: Metered-doseinhaler UV: Ultraviolet

ministered by the intravenous route or by inhalation with nebulizers, even if the benefit of the &-agonist administration by the intravenous administration versus nebulization is still controversial. “-‘* Nebulization of large doses of salbutamol has been extended to ambulatory practice, but continuous intravenous infusion have only been administered for a short period of time in clinics. Intravenous administration of large doses of selective P,-agonists was demonstrated to induce more cardiovascular and metabolic side effects,“-” but tachyphylaxis was not greatly enhanced . ‘X ” We evaluated whether long-term, continuous subcutaneous infusion of salbutamol could improve pulmonary function in subjects with difficult to treat asthma, compared with intermittent nebulization 599

600 Cluzel et al.

J. ALLERGY

I. Characteristics

TABLE

of patients

Onset of asthma (yr)

Age (vr)

Sex

1

33

M

4

2

24

F

3

3 4

48 38

M M

25 ?

5 6 7 8 9 10

34 50 37 54 56 40

F M F M M M

-22 42 6 40 45 3

Patients

Allergic status

Multiple allergies Multiple allergies Multiple allergies -

of salbutamol. A double-blind, placebo-controlled, crossover study was performed, comparing the efficacy, occurrence of side effects, and developmentof tachyphylaxis with ambulatory infusion of salbutamol and with treatment via nebulizer in 10 patients with severe, corticosteroid-dependentasthma. MATERIAL Subjects

CLIN. IMMUNOL. MARCH 1990

AND METHODS

Ten patients (seven men and three women), ranging in age from 24 to 56 years (mean ? SD; 41.4 + 10.3 years), with asthma according to the criteria of the American Thoracic Society,2S were included in the study (Table I). Reversible airway obstruction was found in all patients during the course of their disease. At the time of the study, five subjects did not have an improvement in FEV, <15% of predicted values after inhalation of 200 pg of salbutamol. All subjects had severe asthma defined in our study by the following criteria: (1) an FEV, <70% from predicted values at three different measurements during a month, (2) a history of frequent hospitalizations, more than three within the previous year, and (3) continuous daily corticosteroid requirement with unsuccessful attempts to decrease corticosteroids after maximizing other asthma medications, checking the compliance, and correcting, second, any causes of exacerbations (e.g., sinusitis). Before inclusion in the study, the correct use of B,-agonist MD1 was also verified. Three subjects with asthma were considered allergic, as defined by clinical history and positive skin prick test and serum-specific IgE, determined by classic Phadebas RAST (Pharmacia diagnostics AB, Uppsala, Sweden), with peremial asthma without seasonal exacerbations. The study was approved by the institutional review board.

FEV, at the end of the run in period (% of predicted values)

Prednisolone during run in period (mglday. mean + SD)

28

65 t 80

10

70

32 -c 8

4

56 36

67 I 26 40 k 0

3 9

58 20 64 42 50 60

25 + 52 k 30 t 27 + 25 2 47*

2 3 4 6 5 2

Duration of steroid therapy (vr)

5 10 2 2 4 10

Continuous subcutaneous of salbutamol

infusion

A PROMEDOS El (PROgrammierte MEdikamenten DGSierung Extem, tragbares Gerat, 1 Generation) automatic pump was provided by Siemens Aktiengesellschaft Medical Division (Erlangen, West Germany). It includes a roller pump (maximum flow, 312.5 pl/hr; minimum flow, 3.125 p,l/hr), a 30 ml tank made of high-density polypropylene, and a flexible Luer-Lock (Becton Dickinson, Rutherford, N.J.) pump connection of 0.3 mm internal diameter. The reproducibility of the flow rate was found to be >98%. The catheter was armed by an autosyringe microvolume infusion set (Travenol Laboratories Inc, Hooksett, N.H.) with a 27-gauge needle. The needle was replaced every 5 days. The average flow was 100 pl/hr, and the patients were able to increase the flow of the subcutaneous salbutamol infusion by means of a pulse system. Salbutamol base (Glaxo Laboratories, Paris, France) was used at a concentration of 6 mg/ml in normal saline. The stability of salbutamol in the pump was assessed at 35” C for up to 30 days by means of high-performance liquid chromatography, chromatograph 440 Waters (Millipore SA, St.-Quentin Les Yvelinnes, France). Briefly, the salbutamol solution diluted 1140 was injected in a spherisorb nitrile column (5 pm, 25 x 0.46 cm) (Herbert Knauer KG, Bad Homburg, West Germany). The mobile phase consisted of 5 vol of isopropylic alcohol (Fluka BB, Buchs, Switzerland), 30 vol of 0.05 mol/L of ammonium acetate (Fluka BB), and 65 vol of purified distilled water. The pH of the solution was adjusted at 4.5 with diluted acetic acid. High-performance liquid chromatography was performed at 37” C with a flow rate of 10 ml/mm. Salbutamol was detected at a wavelength of 276 nm by a 450 Waters UV detector (Millipore SA). In a second series of experiments, we examined whether

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salbutamol

infusion

601

polypropylene might be leached into the salbutamol. For this purpose the UV absorption of the salbutamol solution (276 nm) was performedbefore and after 30 days of storage in the pump tank. No modification of the UV absorption of the salbutamol was observed after storage compared with the initial preparation.

Nebulization

NEBULIZED SALBUTAML

of salbutamol

Salbutamol was nebulized with a Pulmo-sonic nebulizer No. 2511 (devilbiss Co., Somerset,Pa.), making it possible to obtain a flow >6 L/min. Salbutamol (7.5 mg) was nebulized three times daily.

Study design and follow-up

CoNTlNuous SC SAL6UTAMJL

moo I 0

Duration

of the patients

Patientshad follow-up for a period of 18weeks,including a 2-weekrun in period during which corticosteroid treatment was stabilized, and three 4-week periods during which placebo and salbutamolwere administeredsubcutaneouslyand by nebulizer in a double-blind, crossover study (Fig. 1). One treatmentperiod consistedof the administration of nebulized and subcutaneousplacebo;during a secondtreatment period, salbutamol was administered subcutaneously and placebo by nebulizer. During a third treatmentperiod, salbutamol was nebulized and placebo was administered subcutaneously. The chronology of these three treatment periods was randomly assignedfor each subject. Each treatment period was followed by a week washout during which patientswere treatedwithout subcutaneousor nebulized salbutamol The following investigations were performed during the study: Before and after each period, pulmonary function tests were done with a Pulmoscan (E. Jaeger, Wtizburg, West Germany) before and after inhalation of 200 kg of salbutamol. The tests were performed 12 hours after any use of a &-agonist. Patients measuredand recorded morning and evening peak flow rates (mini-Wright peak flow meter, Clement Clark International, London, England). Peak flows were measured1 hour after nebulization and were performed three times with the best measurementrecorded. At the end of each treatmentperiod, patients were asked to indicate on a scale ranging from 0 to 5 the global efficacy and comfort of the treatment. All drugs were recordedon daily score cards. With the exception of corticosteroids, patients were allowed to continue their treatmentswithout interruptions. Patients were taught to adapt their daily dose of oral methylprednisolone according to their peak flow rate. Briefly, daily dosesof corticosteroidswere doubled in the presence of exacerbationsof the symptoms for more than 12 hours and/ or a decreaseof the peak flow values by 100 L/r& minimum for more than 1 day. Four days after remission, the dose was gradually reduced by 5 mg every 4 days until the initial dose was reached.In the absenceof symptoms, the dose of corticosteroids was reducedby 5 mg each week until the dose reached 20 mg a day. Inhaled @,-agonistswere allowed with a

I 4

I 8

I t2

1 16

of survey (weeks)

FIG. 1. Study design and follow-up of the patients. Periods of placebo, nebulized salbutamol, or subcutaneous salbutamol sequences were randomly determined, and one example of sequence is illustrated.

maximum of eight inhalations by MD1 per day, even when salbutamol was administeredby nebuiizer or subcutaneous infusion. 5. During this study, patients had a physician visit every 5 days and could call a doctor involved in the protocol any time of the day or night. Continuous infusion and nebulization was started in the presenceot a physician and pulse and blood pressure were checked every 15 minutes for the first 2 hours.

Statistical analysis Statistical analysis was performedby Kruskal-Wallis rank test, and one-way analysis of variance with BMDP (Statistical Software Inc., Los Angeles. Calif. ).

RESULTS Pulmonary function The mean FEV, at the beginning of the study was 47.4 & 17.4% predicted (mean + SD). FEV, was slightly but significantly improved after the run in period (mean + SD, 53.4 k 20.39; p S 0.02, Kruskal-Wallis test) (Fig. 2). The pulmonatryfunction tests at the end of the run in period and at the end of the washout periods, when patients did not receive either subcutaneous or nebulized salbutamol ( Fig. 2), were not significantly different. During the next three periods, there was no significant improvement of FEV, after placebo treatment (mean 2 SD, 50.5 St 16.8 versus 53.2 rt 15.6) (Fig. 2). The percentage of improvement of FEV, was significantly (p S 0.01, Kruskal-Wallis test) greater in periods during which salbutamol was administered by nebulization (mean + SD, 52.5 ? 12.2 versus 62.6 .i: 16.1) or subcutaneous route (mean -+ SD, S 1.4 r! 18.1 ver-

602

Cluzel et al.

J. ALLERGY

25

T

ru,n In placebo

nebullzed

l *

O
1

fun In

eubcutafteoue

plecebo

nebulhd

S.cuteneour

Salbutamol

6

Salbutamol

CLIN. IMMUNOL. MARCH 1990

FIG. 2. Effects of the different periods of treatment on the reversibility of FEV,. A, FEV, expressed as percent of predicted values measured 12 hours before and after the different treatment periods without administration of P,-agonists. 6, FEV, expressed as percent of improvement from prerank test. dicted values during treatment period; n = 10; mean ? SD; *,**Kruskal-Wallis

100

0 run In

placebo

IlebUllUd

wbcutmwu~

Salbutamol FIG. 3. Differences between morning expressed as L/min, for the different

and evening peak flow meter measurements periods; n = 10; mean + SEM.

sus 65.5 + 18), compared to the run in or placebo periods (Fig. 3). There was no significant difference between the run in and placebo periods or the nebulized salbutamol and subcutaneous salbutamol peliOdS.

(variability).

Mean morning and evening PEFRs were similar during all periods (Fig. 3), and the variability between morning and evening PEFR was only slightly and nonsignificantly reduced during the period in which salbutamolwas administeredsubcutaneously(Fig. 4).

VOLUME NUMBER

85 3

Ambulatory

salbutamol

4 p
60 50

603

lus 2% e---W i T +

70

i&xiorr

p
;)-..-a

--4.

.-(,

T

-I--

r placdY0

-l-

.-. - -“‘-‘---ndwiRwd ruboumus

Salbutamo: ran in

plsubo

n8buliMd

subcutrMous

FIG. 5. Average dose of corticosteroids used during different periods, expressed as milligrams of prednisolane per 24 hours for the different periods; n = 10; mean 2 SD. One-way analysis of variance test was used for statistical analysis.

Salbutamol

FIG. 4. Average of the peak flow n = 10: mean ? SD.

meter

measurements;

0 N”

In

placebo

nhm.d

subculmaous

Salbutamol FIG. 6. Increase of FEV, after inhalation of 200 pg of salbutamol after the different periods expressed as percent from predicted

Drug treatment

Oral prednisolone was significantly reduced (p < 0.01, Kruskal-Wallis test) at the end of both periods during which large dosesof salbutamol (nebulization or infusion) were administered by comparison to run in or placebo periods (Fig. 5) with no significant differencesbetweenthe initial values. For the other drugs (theophylline, cromoglycate,andoxytropium bromide

measured 12 hours before and values; n = 10; mean 2 SD.

MDI), there was no difference between riods. Su~ecthre

esseeement

ueatment pe-

of the treatment

Nine patients recorded improvement during the large doses of P,-agonist-treatment periods. On the basisof improved breathing capacity. six patientspreferred the subcutaneousinjection form, and three pre-

604

Cluzel

et al.

ferred the nebulized form. One patient was not improved by either form and disliked both methods of administration. Side effects

When patients received salbutamol in either form, they suffered from tremor, muscular cramps, and tachycardia. These side effects were greater during the subcutaneoussalbutamol-treatmentperiod. For example, 2 hours after the beginning of the treatment, the mean values of the pulse were 83 + 11, 105 + 19, and 118 + 13 with placebo, nebulized salbutamol, and subcutaneous salbutamol, respectively (mean & SD). Local side effects at the injection site have been observed in two patients and consistedof local infection. One of these side effects required systemic antibiotics but did not require stopping of treatment. However, the pump was placed 20 cm apart from the first injection site. Different serum potassiumwas measuredin different treatment periods and was never c2.5 mmol/L (lower normal value for our laboratory, 3.5 mm01/ I,). EKG was performed when serum was <3.5 mmol/L and only demonstratedtachycardia. No patients required potassium replacement, but patients were advised to eat potassium-rich foods. Tolerance to inhaled salbutamol was studied 12 hours after salbutamol infusion or nebulization had been stopped. The reversibility was not significantly different after run in and each treatment period (Fig. 6). DISCUSSION

This study demonstratedthat long-term administration of large dosesof &agonists is well tolerated and elicits a significant decrease of corticosteroid consumption associatedwith an improvement in pulmonary function. No significant differences were found between continuous subcutaneousinfusion and nebulized salbutamol for objective parametersand side effects, whereasthe subjective assessmentof the patients favored subcutaneousinfusion. In our study, the efficacy of long-term treatment with large dosesof salbutamol was demonstratedby a significant reduction in oral corticosteroids. This sparing effect hasalready beenfound with other drugs in asthma.26Furthermore, patients had a significant improvement of FEV, with large dosesof salbutamol associatedwith corticosteroid treatment, not obtained with corticosteroids associatedwith low dose of p2agonist administeredby MDT. We did not observeany carryover effects in the crossover trial. Pulmonary

J. ALLERGY

CLIN. IMMUNOL. MARCH 1990

functions and corticosteroid requirements were not statistically different at the beginning of each period, regardlessof the treatment administered in the previous period. There was no difference among PEFRsin different treatmentperiods. This result was expected, since the patients adjusted methylprednisolone according to PEFR values, and this adjustment rather suggested good compliance to the instructions. The difference between FEV, and PEFR results can be explained by the fact that FEV, was measured 12 hours after the end of the treatment; PEFR was measuredduring the 4 weeks of treatment. Although there was a trend toward a greater subjective improvement of subcutaneous compared to nebulized salbutamol, no significant difference was observed when objective parameterswere measured. Whether the effects of large dosesof &agonist are linked with a reduction of bronchial hyperreactivity is very difficult to determine in this protocol. A direct assessmentof bronchial hyperreactivity was impossible, considering the very low starting value of FEV, of thesepatients. The difference betweenmorning and evening PEFRs (PEFR variability) is not modified, and this supports the absenceof any effect of a large dose of salbutamol on bronchial hyperreactivity.” This is, perhaps in part, due to the late measurement of the peak flow in the morning, 1 hour after nebulization. Comparing peak flow before and after nebulization could have modified PEFR variability. In contrast, the decreaseof corticosteroid consumption, when large doses of &agonists were used, suggestsa beneficial effect of P,-agonist on bronchial inflammation. Both nebulized and subcutaneoussalbutamol elicited similar metabolic and muscular side effects commonly observed with large dosesof P2-agonists.zo, 28 These untoward reactions never causedany patient to stop the treatment. These side effects made it impossible to have a perfectly double-blind study because salbutamol periods were clearly identified, but this problem is routinely observed with &agonists. Two patients using continuous subcutaneousinfusion had a local sepsis,emphasizingthe needfor strict hygienic rules. We did not find any tachyphylaxis to salbutamol, as measuredby reversibility of the FEV, after inhaled salbutamol 12 hours after the end of each period, although it has previously been demonstratedthat intravenous &-agonists can induce tachyphylaxis. 29-3* The lack of tolerance may be related to the concommitant corticosteroid treatment.33.34 The drawback to nebulization use is that this kind of administration was time consuming and inconve-

VOLUME NUMBER

85 3

nient in professional life. Moreover, some patients were noncompliant with the use of nebulizers. Sleeping problems induced by the position of the pump on the stomach and difficulties when patients showered were the main problems reported with the use of subcutaneous infusion. In conclusion, patient education and steroids (inhaled or systemics) are first therapeutic options in moderate to severe asthma. However, some patients with severe asthma do not respond to steroid therapy alone. In this subset of patients, administration of large doses of &-agonist, in addition to steroid therapy, was able to improve respiratory function. However, long-term benefits after the end of the treatment remain to be demonstrated. Since the cost of the subcutaneous infusion is much greater than cost of the nebulized form and since the cost/benefit ratio is lower with injection, this form of treatment should be reserved for patients with severe asthma after an unsuccessful trial with nebulized salbutamol. Since this study demonstrated the safety of continuous subcutaneous infusion of salbutamol for 3 weeks, we suggest that the possible long-term benefits of this form should be investigated further. We are grateful to Dr. Franklin N. Adkinson and Dr. Michael E. Weiss for excellent help in preparing this manuscript. REfEREMCES I

2.

3.

4. 5. 6.

7.

8.

9.

Wyllie AH, Poznansky MC, Gordon ACH. Glucocotticostero&resistant asthma: evidence for defect in mononuclear cells. In: Kay AB, ed. Asthma: clinical pharmacology and therapeutic progress. Oxford: Blackwell, 1986:306-13. Carmichael J. Paterson IC, Diaz P, Cromptom GK, Kay AB, Grant IWB. Corticosteroid resistance in asthma. Br Med J 1981;282:1419-22. Turner-Watwick M. Clinical patterns of responsiveness to corticosteroids. In: Kay AB, ed. Asthma: clinical pharmacology and therapeutic progress. Oxford: Blackwell, 1986:347-55. Turner-Warwick M. On observing patterns of airflow obstruction in chronic asthma.Br J Chest Dis 1977;71:73-8. Hetzel MR, Clark TJH. Adult asthma. In: Clark TJH, Godfrey S, eds. Asthma. London: Chapman & Hall, 1983:457-89. Patterson R, Greenberger PA, Grammer LC. Some indications for methylprednisolone for asthma or other severe allergic disease. J ALLERGYCLANIMMUNOL1986;77:686-90. Willey RF, Fergusson RJ, Godden DJ, Crompton GK, Grant IWB. Comparison of oral prednisolone and intramuscular depot triamcinolone in patients with severe chronic asthma. Thorax 1984;39:340-44. Cockcroft DW, Murdock KY. Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine. J ALLERGYCLIN IMMUNOL1987;79:734-40. Cullum VA, Farmer JB, Jack D, Levy GP. Salbutamol: a new, selective @drencceptive receptor stimulant. Br J Pharmacol 1969:35:371-6.

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saibu!amoi

wk~s;nn

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IO. Larsson S, Svedmyr N. Bronchodilatop rfieci anJ stdc effects by &adrenoreceptors stimulants by different n~~d<~hot administration: tablets, metered aerosol. and ~combination therapy-a study with salbutamol in a\thmaricr “riiv Rev Rehpir Dis 1969;116:861-9. 11. Ahrens S. Smith Cm. Albuterol: an adrenergtc agent tor use m the treatment of asthma. Pharmacology. phalrtlacokinet~a, and clinical use. Pharmacotherapy 1984:4. IOS-20. 12. Bouquet J, Clauzel AM, Michel FB. Adrenergic agonists in asthma. In: Kaliner MA, Barnes PJ, eds. The arrway,, neural control in health and disease, vol 33. New York Marcel Dekker, 1988:119-57. of sal13. Cayton RM, Webber B. Paterson JW. A roqxwn butamol given by pressure-packed aerosols or nehulization via IPPB in acute asthma. Br J Dis Chest 19X1:7:1:1?2-4 14. Crompton G. Comparison of salbutamol given intravenously and by intermittent pressure breathing in Ilte-threatening asthma. Br Med J 1979;278:848. 15. Pierce RJ. Payne CR, Williams SJ, Derubon DM. Clark TJH. Comparison of intravenous and inhaled terbutaline In the treatment of asthma. Chest 1981;79:506-IO. 16. Williams S. Seaton A. Intravenous or inhaled
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chodilator action of alhuterol produced by chronic administration. Am Rev Respir Dis 1977;116:871-7. 32. Amaud A, Charpin J. Interaction between corticosteroids and B-agonists in acute asthma. Eur J Respir Dis 1982;122: 12631. 33. Coffey RG, Logsdon PJ, Middleton E Jr. Leukocyte adenyl

CLIN. IMMUNOL. MARCH 1990

cyclase and ATPase in asthma: effect of corticosteroid therapy. Chest 1973;63:25-7. 34. Davies AO, Letkowitz RJ. In vitro desensitization of padrenergic receptors in human neutrophils: attenuation by corticosteroids. J Clin Invest 1983;71:565-71.

Comparison of the efficacy and side effects of aqueous steroid nasal spray (budesonide) and allergen-injection therapy (Pollinex-R) in the treatment of seasonal allergic rhinoconjunctivitis E. F. Juniper, MSc, P. A. Kline, RN, E. H. Ramsdale, F. E. Hargreave, MD Hamilton, Ontario, Canada

BM, and

The efticacy and side effects of two approaches to the treatment of ragweed pollen-induced rhinoconjunctivitis were compared in a double-blind, parallel-group trial. Sixty ragweed-sensitive adults were randomized either to a course of four Pollinex-R hyposensitization injections during the 6 weeks before the ragweed-pollen season, or to bua!esonide aqueous nasal steroid spray, 400 pg daily, throughout the season. A double-dummy technique was used to achieve blinding. During the ragweed-pollen season, troublesome nasal symptoms were treated with terfenadine, 60 mg, when treatment was needed, up to 240 mg daily, and eye symptoms were treated with naphazoline eye drops, when treatment was needed, up to four times daily. Every day, subjects recorded the severity of nasal and eye symptoms and medication use in a diary. Fourteen of the subjects receiving Pollinex-R were unable to complete the course of injections because of systemic or large local reactions. Eight subjects withdrew during the pollen season because of severe rhinitis; all subjects had received Pollinex-R. Subjects in the budesonide-treated group had minimal nasal symptoms and used very little tegenadine, compared with subjects in the Pollinex-R-treated group (p < 0.0001). Eye symptoms and eye drop use were similar in the two treatment groups. No clinically important side effects were reported by the subjects receiving budesonide. The results of this study suggest that aqueous budesonide nasal spray is markedly more effective than Pollinex-R in controlling symptoms of seasonal rhinitis while the side effects and inconvenience of immunotherapy are avoided. (J ALLERGY CLIN IMMUNOL 1990;85:606-11.)

From Firestone Regional Chest and Allergy Clinic, St Joseph’s Hospital, Department of Clinical Epidemiology and Biostatistics, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Supported by a grant from Astra Pharmaceuticals Canada, Ltd., Mississauga, Ontario, Canada. Received for publication June 20, 1989. Revised Sept. 20, 1989. Accepted for publication Sept. 25, 1989. Reprint requests: Elizabeth F. Juniper MCSP, MSc, Department of Clinical Epidemiology and Biostatistics, McMaster University Medical Centm, 1200 Main St., West, Hamilton, Ontario, Canada L8N 325. 111117559

606

The regular use of inhaled steroid nasal sprays is a very effective approach to the treatment of seasonal allergic rhinitis.’ Two recent studies have demonstrated that these sprays are more effective than the new nonsedativeantihistamines2~3 and that, evenwhen these sprays are used separately, they are just as effective as when they are taken in combination with an antihistamine.4v5 In recent years, the nasal sprays have becomeavailable as an aqueousaerosoland have been demonstratedto be just as effective as the original Freon-propelledaerosolsand to reducethe drying ‘and caking of the nasal mucosa, a side effect of the