A trial of ranitidine in asthmatic children and ... · acid reflux by treatment with the H 2-blocker ranitidine, taken as a single dose in the evening during four weeks, to see whether

Eur Reaplr J 1992, 6, 201-208

A trial of ranitidine in asthmatic children and adolescents with or without pathological gastro-oesophageal reflux

P.M. Gustafsson*, N-I.M. Kjellman*, L. Tibbling**

A trial of ranitidine in asthmatic children and adolescents with or without patho· logical gastro-oesop!Jageal reflux. P.M. Gustafsson, N-l.M. Kjellman, L. Tibbling.

Depts of • Paediatrics and • • Otorhinolaryngology Faculty of Health Sciences University Hospital LinkOping

ABSTRACT: In order to study tbe Importance of gastro-oesophageal reflux (GOR) as a trigger of asthma the effect of lohlblfioo or gastric acid secretion on asthma was assessed In a double-blind, cross-over, placcbo-cootrollcd trial over four weeks In 37 children and adolescents (mean age 14 yrs) with bronchial asthma.

Sweden.

Correspondence: Dr P.M. Gustafsson Dept of Paediatrics Ranitldlne 300 mg, (ISO mg If B.W, was <40 kg) was given as a single even.lng

dose during four weeks. lo previous Investigations 18 of the 37 patients had been shown to have pathological GOR by 24 h pH monitoring In the oesopha­gus. The remaining 19 patients with normal GOR served as controls for possible effects or ranltidine on asthma, not related to reduction or GOR.

University Hospital S-581 85 LinkOping Sweden.

Keywords: Adolescents; bronchial asthma; children; gastro-oesophageal re­flux; H2-receptor antagonists; ranitidine.

A modest (30%) but statistically significant reduction of nocturnal asthma symptoms was produced by ranltidlne in the patients with pathological GOR when compared to those with normal GOR. There was a significant correla­tion between the improvement In asthma symptoms and the degree of acid reflux. Side-effects of ranltid.ine were negligible.

Received: June 5, 1990; accepted after revision August 22, 1991.

Acid reflux appears to be only a weak stimulus for bronchoconstrlction In children and adolescents with bronchial asthma and pathological GOR. Further confirmative trials with more potent inhibitors of gastric acid secre­tion are, however, warranted.

This study was supported by a grant from the Swedish Medical Research Council, project No. 17X·4260, and by Glaxo Pharmaceuticals, Sweden Ltd. Eur Respir J., 1992, 5, 201-206.

Pathological gastro-oesophageal reflux (GOR) and oesophageal dysfunction (OD) are common findings in children and adults with bronchial asthma [1-9]. There has been much discussion of whether GOR has a negative influence as an inducer and trigger of asthma or whether it is merely a eo-finding in asthma [9-10]. Studies in which asthma symptoms have been alleviated by medical (11-15] or surgical (16-20] treat­ment of GOR support the idea of a cause and effect relationship between GOR and asthma.

The aim of the present investigation was to see whether reflux of gastric acid was important for asthma, especially for nocturnal and morning asthma symptoms, in an unselected group of children and adolescents with bronchial asthma and pathological GOR. Therefore, we studied the reduction in gastric acid reflux by treatment with the H

2-blocker ranitidine,

taken as a single dose in the evening during four weeks, to see whether it could improve asthma symp­toms and lung function. We thought that a reduction of nocturnal or morning asthma symptoms by at least 50% would indicate that acid reflux is of major im­portance for asthma. Asthmatic subjects with normal GOR served as controls, should there be a beneficial or negative effect of ranitidine on asthma not related to its effect on gastric acid reflux.

Patients and methods

Forty two children and adolescents with bronchial asthma were asked to take part in a randomized, double-blind, placebo-controlled, cross-over study of the effect of ranitidine (150-300 mg) taken orally once a day in the evening over four weeks. They had all previously undergone a 24 h two level pH moni­toring of the oesophagus 0-14 months (mean 3.3 months) prior to the present ranitidine trial, in another study aimed at elucidating the prevalence of pathologi­cal GOR in children and adolescents with moderate or severe bronchial asthma [21]. They had also been investigated with an oesophageal acid perfusion test (APT) (8] 3.5-20 months (mean 9.9 months) before the ranitidine trial. Forty of the 42 subjects agreed to participate and 37 subjects, 22 males and 15 females, completed the study (table 1). All participants were using regular asthma medication (table 1) and all of them inhaled beta2-agonists when required.

In a questionnaire, which was filled in before the trial commenced, symptoms of acid regurgitation, heartburn or dysphagia were graded from 0 to Ill. Grade 0 indicated no symptoms; grade I infrequent and mild symptoms; grade II symptoms quite frequently, often requiring some kind of relief, e.g. drinking milk

202 P.M. OUSTAFSSON, N·I.M. KJELLMAN, L. TIBBLINO

or taking antacids; and grade III disabling symptoms (table 1). Nocturnal and morning asthma was graded I-IV. Grade I denoted no asthma attacks in the night or in the morning; grade II denoted asthma attacks 1-9 nights or mornings; grade Ill denoted asthma attacks 10-99 nights or mornings, and grade IV denoted asthma attacks during ll!:100 nights or morn­ings over the previous year.

tablets before each treatment period, each containing 150 mg ranitidine or placebo, respectively. These pa­tients were instructed to take two tablets in the evening, one hour before going to bed, during the treatment periods.

The patients with a B.W. <40 kg were given 4.30 mg (mean; range 3.85-5.00 mg) ranitidine·kg·1 B.W. per day and the heavier subjects were given 5.63 mg

Table 1. - Demographic data, percentage total reflux time, number of patients with positive acid perfuslon test (APT), oesophageal symptoms, asthma history, and asthma medication in the patients with normal and those with pathological GOR

Male/female Age yrs, mean (range) Asthma duration yrs, mean (range) Reflux time %, mean:tSEM

Positive APT n Heartburn grade n

Regurgitation grade n

Dysphagia grade n

NoctumaVmorning asthma grade n

Medication n Sodiul)l cromoglycate Inhaled steroids Oral beta

2-agonists

Oral theophylline Oral steroids

0 I II Ill 0 I

II Ill

0 I

II Ill

I 11

Ill IV

Normal GOR n=19

9/10 14.2 (10.0-20.8) 12.5 (3.2-19.8) 0.5:t0.1

6 7 9 3 0

6 10 3 0

16 2 1 0

1 2 8 8

9 7 9

13 1

Pathological GOR n=18

13/5 13.9 (9.5-17.5) 11.3 (3.Cr16.7)

2.7:t0.3

7 4

12 2 0

5 11 2 0

11 6 1 0

0 1 8 9

14 5

10 12 1

GOR: gastro-oesopbageal reflux; n: number of patients.

Eighteen of the 37 subjects (49%) had pathological reflux according to the 24 h pH test, i.e. reflux to the distal oesophagus during more than 1% of the record­ing period (22], and 13 subjects (35%) had a positive APT, i.e. heartburn Jr chest pain during acid infusion, at the pretrial oesophageal investigation [8]. Th~ study was arranged as a randomized, double­

blind, cross-over trial with a two week run-in period before the first four week treatment period and a two week wash-out period before the second treatment pe­riod. Patients with a body weight (B.W.) <40 kg were supplied with 28 tablets before each treatment period, containing either 150 mg ranitidine per tablet, or a pla­cebo of identical appearance. The patients were in­structed to take one tablet one hour before going to bed every evening during the treatment periods. Pa­tients with a B.W. of ll!:40 kg were supplied with 56

(mean; range 3.61-7.32 mg) ranitidine·kg·1 B.W. per day.

The main evaluation of the trial was based on daily record cards. The patients were instructed to record asthma symptoms and peak expiratory flow rate (PEFR), using a Wright mini peak flow meter twice daily. Each morning the patients made separate notes on any asthma symptoms, which had appeared during the previous night and the morning hours, and performed three PEFR recordings before medication, the highest of these three values being registered. In the evening they made a note of the degree of wheez­ing, coughing, and restriction in acitivities that had occurred during the day. They were also instructed to perform three PEFR recordings and to note the highest of the three. All symptoms were graded from 0 to 3 points. Zero denoted no symptoms at all and

RANITIDINE, REFLUX AND ASTIIMA 203

3 points indicated very severe symptoms. The maxi­mum daily asthma symptom score was 15.

All medication taken during the day was recorded. The patients were told to note possible adverse reactions to the treatment in their record cards.

The patients were seen at the clinic by one doctor (PMG) on three occasions: i.e. on the day after completion of the run-in period, and on the day after completion of each of the two treatment periods. On these occasions spirometry (forced expiratory volume in one second (FEV

1)) was performed with a dry

sealed spirometer (Vicatest 5•, Mijnhardts, The Netherlands), as well as a bronchial histamine chal­lenge. Before evaluation of data, FEV

1 and PEFR were

transformed into percentage of the predicted values [23].

The histamine challenge was performed if the FEV

1 was >70% of the predicted FEY values [23].

The same jet nebulizer (Pari Boy•, Paul Ritzau Pari­Werk GmbH, FRG) was used throughout the trial. After checking that the FEV

1 was stable within 5%,

the patients inhaled saline for 2 min and the FEV1 recorded after saline was used as baseline. Histamine chloride solutions were then inhaled by 2 min tidal volume breathing at 5 min intervals, starting with a concentration of 0.03 mg·mP and increasing by fourfold increments up to 8 mg·ml·1 or until a fall in FEV

1 by at least 20% was recorded. The provoking

concentration of histamine causing a 20% fall in FEV1 (PC

20Hi) was calculated by logarithmic interpolation.

At the three visits to the clinic asthma symptoms and oesophageal symptoms over the previous week were evaluated by means of a Visual Analogue Scale (V AS). Symptoms were scored on a VAS ranging from 0-10 cm, with 1 cm marks between the end­points. At the last visit to the clinic the patients were asked which treatment period they had preferred as regards their asthma symptoms.

Venous blood samples for blood cell count, serum concentrations of electrolytes, creatinine, urea, bi­lirubin, liver transaminases, alkaline phosphatases, and a urinary dip stick, were taken at each visit to the clinic.

Statistical analysis

The trial was dimensioned with an aim of obtain­ing a 90% chance of detecting a 50% reduction of nocturnal and morning asthma symptoms. The Wilcoxon's signed rank test was used for comparison of the placebo and the ranitidine treatment periods separately in the patients with and in those without pathological GOR. A comparison between the two groups of patients, regarding the effect of ranitidine on asthma, i.e. the difference in asthma symptom score between the ranitidine and placebo periods, was further performed and analysed by the Mann-Whitney U-test. A p-value <0.05 was regarded as significant. Two-tailed tests were used throughout. Regression analysis was used to see if the difference in asthma symptoms between the ranitidine and

placebo periods correlated with percentage reflux time at the previous oesophageal pH monitoring.

Ethics

The study was approved by the Ethics Committee for Human Research at the University Hospital of Linkoping and written consent was obtained from all subjects and their parents.

Results

Comparison between the complete four week ranitidine and the placebo period showed no signifi­cant reduction of asthma symptoms or improvement of morning or evening PEFR during ranitidine treat­ment in either the patients with pathological or in those with normal GOR. The patients with pathologi­cal acid reflux had a beneficial effect on nocturnal asthma symptoms significantly more often (fig. 1) than those with normal reflux. The regression analysis showed significant positive correlations between the total percentage reflux time at pH moni­toring and the reduction of nocturnal asthma symptom score (r=0.46; d.f.=35; p<0.01), nocturnal-morning asthma symptoms by the V AS (r=0.39; p<0.05) (fig. 2), and total asthma symptom score (r=0.35; p<O.OS) (fig. 3) during ranitidine treatment.

0.6

~ 0

~ 0.4

CIS E

i eo c .._

~ z '-NS....J

'--- p=0.016 -~ Pathol. GOR Normal GOR

n=18 n=19 Fig. 1. - Nocturnal asthma symptom score during the placebo and the ranitidine treatment periods, and the difference in score between the two periods, in the patients with pathological and in those with normal gastro-oesophageal reflux (GOR). Mean:tsEM are given. Statistical comparison between the placebo and the ranitidine periods was performed separately for the two groups of patients by the Wilcoxon's signed rank test. The effect of treat· ment (ranitidine-placebo score) was compared between the two groups by the Mann-Whitney U-test. c:::J: placebo; rzl: ranitidine; D : ranitidine-placebo.

The patients with pathological APT (n=13) did not improve during ranitidine treatment significantly more than those with a negative APT.

FEV1 did not change between visits. As a result of the low FEY 1 values, histamine threshold

204 P.M. GUSTAFSSON, N-I.M. KJELLMAN, L. TIBBLING

measurements after both treatment periods were re­stricted to 12 of the 19 patients with normal GOR, and to 10 of the 18 patients with pathological reflux. No significant change in bronchial histamine reactivity was seen between the two test occasions in either patient group (table 2). The .ranitidine period was not preferred significantly more often than the placebo period in either group (table 2).

Pathol. GOR n=18

NS

Normal GOR n=19

Fig 2. - Nocturnal/morning asthma symptom score according to visual analogue scale (VAS) over the last week of the placebo period and of the last week of the ranitidine period, and the differ­ence in score between the two periods, in the patients with pathological and in those with normal gastro-ocsophageal reflux (GOR). MeausEM are given. Statistical comparison between the placebo and the ranitid ine periods was performed separately for the two groups of patients by the Wllcoxon's signed rank test. The effect of treatment (ranitidine-placcbo score) was compared between the two groups by the Mann-Whitney U-test. Ns: nonsignificant; D : placebo; IZZI : ranitidine; - : ranitidine­placebo.

The V AS disclosed only mild and infrequent oesophageal symptoms in both groups during the placebo period and there was no significant difference between the two periods in either group of patients.

Three subjects reported mild side-effects during the ranitidine period, one with irregular and loose stools, the second one had abdominal pain twice dur­ing the first days of treatment, and the third com­plained of morning fatigue more than usual. Five subjects reported possible side-effects during the pla­cebo period: one complained of hoarseness, the sec­ond one had slight tremor initially, the third one developed urticaria, the fourth had epigastric pain on a few occasions and the fifth patient had a slight head­ache during the first days of treatment.

No systematic or individual changes in the blood biochemistry or urinary tests were seen between the three test occasions. One patient had high serum creatinine (110 J.Lmol-1·1; reference value: 40-100 J.Lmol-/'1), on all three occasions. She had normal urinary dip stick findings and a normal blood pressure. At follow-up, a radiological examination of the kidneys was performed showing small kidneys, possibly due to previous pyelonephritis.

3

L-Ns .....J

-1 ~------Ns------_j

Pathol. GOR n=18

Normal GOR n=19

Fig. 3. - Total asthma symptom score during the placebo and the ranitidine treatment periods, and the difference in score between the two periods, in the patients with pathological and in those with normal gastro-oesophageal reflux (GOR). Mean:tSllM ate given. Statistical comparison between the placebo and the ranitidine periods was performed separately for the two groups of patients by the Wilcoxon's signed rank test. The effect of treatment (ranitidine-placebo score) was compared between the two aroups by the Mann-Whitney U-test. Ns: nonsignificant.CJ: placebo; I22J: ranitidine; - : ranitidine-placebo.

Table 2. - Bronchial histamine reactivity after the ranitidine and the placebo periods and the preference of treatment periods In the patients with pathological (n=18} and those with normal GOR (n=19)

PC20

Hi mg·ml·' After ranitidine period

After placebo period

Preferred period Placebo Ranitidine Neither

Pathological GOR Normal GOR

0.54:0.17 J NS 0.58::t:0.10 J NS

0.67:0.10 0.99:0.27

4 5 9

NS

5 2

12

Bronchial histamine challenge was performed after both periods in 10 patients with pathological and in 12 patients with normal GOR. GOR: gastro-oesophageal reflux; PC

20Hi:

provoking dose of histamine causing a 20% fall in forced expiratory volume in one second.

Discussion

This study in children and adolescents with bron· chial asthma shows that an oral dose of ranitidine taken in the evening, in addition to ordinary asthma medication, produced a statistically significant, but very modest reduction (30%) of nocturnal asthma symptoms in patients with pathological GOR when compared to those with normal GOR. Regression analysis disclosed significant positive correlations

RANITIDINE, REFLUX AND ASTIIMA 205

between the improvement of nocturnal, morning and total asthma symptoms and the degree of pathological GOR at oesophageal pH monitoring. No beneficial effect of ranitidine was seen on morning or evening PEFR, FEV

1 or bronchial histamine reactivity.

A positive APT did not predict a positive response to ranitidine, suggesting that the effect of ranitidine treatment on asthma was more closely related to the degree of acid reflux, than to the finding of acid sensitivity of the oesophagus.

Three controlled studies on the effects of H2-

blockers on asthma symptoms in adult patients with bronchial asthma and pathological GOR have previ­ously been published [3, 12, 15], but there is no con­trolled study of the effect on asthma by reduction of gastric acid reflux by H2-blocker therapy in asthmatic children with GOR.

NAGEL et al. [3] treated 15 adult asthmatics with pathological GOR with ranitidine 300 mg in the morn­ing and 150 mg in the evening for seven days in a placebo-controlled study. No improvement of asthma symptoms or PEFR was seen, which might be due to the very short duration of that trial. In the study by GOODALL et al. [12] 18 adults with bronchial asthma and symptoms of pathological GOR were evaluated in a double-blind, cross-over trial over six weeks with cimetidine 200 mg three times daily and 400 mg at night. A significant reduction in reflux symptoms, and nocturnal asthma symptom scores, and a minor increase in the last PEFR reading during the day, were found during the cimetidine period. In the study by EKSTROM et al. [15], 48 adult asthmatics with symp­toms of reflux were given ranitidine 150 mg twice daily and placebo, respectively, in a double-blind, cross-over fashion, over a four week period. A signifi­cant reduction in reflux symptoms and in nocturnal asthma scores was seen during the ranitidine period. However, the positive results were confined to a subgroup of 27 patients with a history of reflux symp­toms preceding episodes of asthma symptoms [15].

One explanation for the limited effect of gastric acid secretion inhibition on asthma in the present study could be that ranitidine did not sufficiently inhibit acid secretion and consequently did not reduce acid reflux enough. We gave the patients 300/150 mg ranitidine as a single evening dose as it had been reported that a single dose of 300 mg ranitidine produces an equivalent inhibition of gastric acid secretion to 150 mg ranitidine twice daily [24). RUTH et al. [25] compared the effect on oesophageal acid­ity of 20 mg omeprazole once daily with that of 150 mg ranitidine twice daily, by 24 h oesophageal pH monitoring in patients with ulcerative oesophagitis. The percentage reflux time (pH <4.0) was reduced by 41% during ranitidine treatment and by 82% during omeprazole treatment [25], indicating that pathologi­cal acid reflux is not completely abolished by a sin­gle evening dose of ranitidine.

Secondly, there have been some controversies in the literature as to whether asthma can deteriorate from H2-receptor blockade due to promotion of

histamine release [26, 27] and increase of bronchial tone [28-30]. Ranitidine may, thus, have a beneficial effect on asthma symptoms in patients with patho­logical GOR by reducing acid reflux and a negative effect on asthma from H2-receptor blockade on mediator cells and bronchial smooth muscle.

The present trial indicates that reduction of acid reflux may improve asthma symptoms, but the study is not large enough to give a firm understanding of the size of treatment effects. We have in fact detected a reduction in nocturnal asthma symptoms that was supposedly obtained by a reduction in acid reflux. The size of the reduction in nocturnal asthma score is estimated to be approximately 30%. However, judging from a 90% confidence interval, the true percentage reduction can be practically null in one extreme and beyond 60% in the other. Thus, the size of the effect and its clinical significance are not effectively determined in this study.

In summary, the H2-blocker ranitidine, taken as a single evening dose over a four week period by asthmatic children and adolescents, produced a small reduction in nocturnal asthma symptoms. There was a significant correlation between the improvement in asthma symptoms and the degree of acid reflux. The modest improvement during ranitidine treatment suggests that mild or moderately severe pathological acid reflux, which is often seen in children and adolescents with asthma, is not of major importance in asthma. The small size of the present study and the inability of H2-blockers to completely abolish acid reflux, however, preclude conclusive statements on the importance of pathological GOR for childhood and adolescent asthma. Therefore, further studies with more potent inhibitors of gastric acid secretion and acid reflux, such as omeprazole, are suggested.

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