managing heartburn at the ‘base’ of the gerd ‘iceberg’: effervescent ranitidine 150 mg b.d....

Managing heartburn at the `base' of the GERD `iceberg':effervescent ranitidine 150 mg b.d. provides fasterand better heartburn relief than antacids

D. EARNEST*, M. ROBINSON , S. RODRIGUEZ-STANLEY , A. A. CIOCIOLAà , P. JAFFE*,

M. T. SILVER§, C. S. KLEOUDIS§ & R. H. MURDOCK§

*University of Arizona Health Sciences Center, Tucson, AZ, USA; Oklahoma Foundation for Digestive Research, University

of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; àWarner Lambert Company, Morris Plains, NJ, USA; and

§Glaxo Wellcome Inc., Research Triangle Park, NC, USA

Accepted for publication 7 March 2000

INTRODUCTION

Many individuals with heartburn do not seek medical

care for their symptoms, but instead regularly self-

medicate with over-the-counter antacids. Heartburn is

generally attributed to the re¯ux of acidic gastric contents

into the oesophagus when intragastric pressure exceeds

the pressure exerted by the lower oesophageal sphincter,

particularly during spontaneous relaxations.1±3 Ant-

acids have been thought to provide rapid relief of

heartburn by neutralizing stomach acid, but more recent

data localize antacid effects to the oesophageal lumen.4±8

In contrast, H2-receptor antagonists such as ranitidine

provide relief of heartburn by inhibiting acid secretion,

thereby subsequently elevating intragastric pH and

SUMMARY

Background: Many individuals with heartburn self-med-

icate with antacids for relief of their symptoms.

Aim: To compare ef®cacy of effervescent ranitidine to

as-needed calcium carbonate antacids in subjects who

self-treat heartburn.

Methods: A total of 155 subjects with frequent antacid-

responsive heartburn were randomized to receive

effervescent ranitidine 150 mg tablets b.d., or as-needed

calcium carbonate 750 mg for 12 weeks. Endoscopic

oesophagitis severity and mucosal histology were

assessed at baseline, and at weeks 6 and 12. Heartburn

frequency, severity, and antacid consumption were

recorded daily, and quality of life was assessed at

baseline, and at weeks 6 and 12.

Results: Heartburn frequency and severity were signi®-

cantly decreased after 1 day of ranitidine (P < 0.02). By

week 6, ranitidine had signi®cantly decreased rescue

antacid consumption (7.3 tablets, P < 0.001) vs. ant-

acids (14.1 tablets). Endoscopic oesophagitis healing

(£ grade 1) was signi®cantly better with ranitidine

(55%, P � 0.022) vs. antacids (29%). Quality of life was

improved by both treatments; however, ranitidine was

numerically superior for all quality of life parameters,

statistically superior for several quality of life indices at

week 6 and for the pain-related index by week 12

(P < 0.05).

Conclusions: For subjects self-administering antacids for

chronic heartburn, effervescent ranitidine 150 mg b.d.

is more effective than antacids in reducing heartburn,

healing erosive oesophagitis, alleviating pain, and

improving quality of life.

Correspondence to: Dr S. Rodriguez-Stanley, The Oklahoma Foundation for

Digestive Research, 711 Stanton L Young Blvd, Suite 624, Oklahoma City,

OK 73104, USA.E-mail: [email protected]

Aliment Pharmacol Ther 2000; 14: 911±918.

Ó 2000 Blackwell Science Ltd 911

reducing the volume of gastric contents and acid

available for re¯ux into the oesophagus.9

Twice-daily administration of the tablet formulation of

ranitidine 150 mg has been shown to relieve heartburn

in patients with gastro-oesophageal re¯ux disease

(GERD) within the ®rst 2 weeks of initiating treatment.9

Effervescent ranitidine tablets are bioequivalent to the

usual ranitidine tablets and share the same indications

with other oral ranitidine products. The currently

approved use of the oral dose of effervescent ranitidine

tablets for the symptomatic relief of GERD is 150 mg

b.d. Effervescent ranitidine offers rapid heartburn relief,

a property supported by its pharmacokinetic pro®le,

which demonstrates rapid antisecretory effects, and

may also offer long-term relief and improvement in

quality of life scores. In addition, patients may prefer an

effervescent liquid formulation of an antisecretory

medication compared to tablets.

This randomized, double-blind, two-centre, parallel

trial compared the safety and ef®cacy of 150 mg

effervescent ranitidine tablets with 750 mg calcium

carbonate antacids taken as needed. The included

subjects self-medicated with antacids for control of

heartburn, and had not previously undergone diagnos-

tic testing or therapeutic management with prescription

drugs for GERD. Thus, these subjects represent the large

number of individuals in the community who self-treat

for heartburn and are perhaps also similar to those

presenting to their primary care physicians with

symptoms suggesting a clinical diagnosis of GERD. In

order to determine the severity of GERD and the

characteristics of any anatomic and physiological

abnormalities present, subjects in this study underwent

a series of special diagnostic tests including upper

gastrointestinal endoscopy with biopsies, oesophageal

motility testing, 24 h pH monitoring, and tests for

oesophageal sensory perception. Results of these studies

have been published previously along with demogra-

phic data from these subjects.10 This report presents

data regarding the ef®cacy of treatment with efferves-

cent ranitidine 150 mg tablets in heartburn sufferers

previously using only antacids for symptom relief.

METHODS

Study design

Adults 18 years of age or older with at least a 3-month

history of antacid-responsive heartburn and who had

not undergone previous diagnostic evaluation or

received prescription therapy were recruited by adver-

tisement and paid a stipend for participation. This

randomized, double-blind, parallel group study was

conducted at two sites in the United States. Eligible

subjects were required to experience heartburn on at

least four of seven consecutive days during the run-in

observation period. Any clinically signi®cant disease

other than uncomplicated GERD found at baseline

diagnostic evaluation led to exclusion from this trial.

Exclusions included endoscopic identi®cation of gastric

or duodenal ulcer ³ 5 mm with any perceptible depth,

any histological evidence of high grade dysplasia related

to Barrett's oesophagus, any manometrically demon-

strated primary oesophageal motility disorder, or

oesophagitis not related to re¯ux. Subjects were also

excluded for use of prescription pro-motility medications

within 30 days prior to the study, use of systemic

corticosteroids, anticholinergics, anticoagulants, an-

tineoplastics, or regular use of non-steroidal anti-

in¯ammatory drugs. The Institutional Review Boards

approved the protocol at each study site, and all patients

provided written informed consent.

Prior to being randomized to treatment, medical

histories, physical examinations and laboratory testing

were accomplished. Oesophago-gastroduodenoscopy

(EGD) was performed to determine baseline abnormal-

ities of the upper gastrointestinal mucosa and to grade

any oesophagitis. Oesophageal grading used an adapted

Hetzel endoscopic scoring scale: grade 0 � normal;

grade 1 � erythema, hyperemia, or friability with no

macroscopic erosions/ulcerations; grade 2 � erosions/

ulcerations involving < 10% of the mucosal surface of

the distal 5 cm of the oesophagus; grade 3 � erosions/

ulcerations involving between 10% and 50% of the

mucosal surface of the distal 5 cm of the oesophagus;

and grade 4 � erosions/ulcerations involving > 50% of

the mucosal surface of the distal 5 cm of the oesoph-

agus.11 Erosive oesophagitis was de®ned as an oeso-

phageal grade of 2, 3, or 4.

Following a 1-week run-in observation period during

which all subjects used calcium carbonate antacids and

documented the frequency of heartburn episodes,

eligible subjects with heartburn on at least four out of

seven consecutive days began a 14-day baseline phase

to characterize the severity of their re¯ux disease.

Subjects were instructed to swallow up to two tablets of

the supplied antacid as needed for each heartburn

episode, but not to exceed 10 tablets in 24-h. No other

912 D. EARNEST et al.

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 911±918

antacids or other medications that might affect the

course of GERD were permitted during the trial. Any

lifestyle modi®cations being practised were determined

at baseline and subjects were instructed to continue

these without modi®cation throughout the trial. Day-

time and night-time heartburn frequency and severity

and antacid consumption were recorded daily on diary

cards. Patients assessed heartburn severity by using a

visual analogue scale (VAS) from 0 (no heartburn) to

100 (unbearable heartburn).

All subjects who entered the 2-week baseline observa-

tion period were randomly assigned to receive a 12-

week course of either: effervescent ranitidine tablets

150 mg (ANC of 4 mEq) twice daily (breakfast and

bedtime) dissolved in 8 oz of water, plus placebo

swallowable calcium carbonate antacids as needed

(placebo antacids); or swallowable calcium carbonate

antacids 750 mg (ANC of 10 mEq) as needed (study

antacids), plus placebo effervescent ranitidine tablets

dissolved in 8 oz of water twice daily (breakfast and

bedtime). The calcium carbonate antacids and placebo

antacids were formulated as swallowable tablets to

assure that placebo effects would not be unduly

ampli®ed by additional antacid effects of admixture with

saliva in the oesophageal lumen. Follow-up visits and

oesophago-gastroduodenoscopies were scheduled after 6

and 12 weeks of treatment. At each endoscopy, biopsies

were taken at the gastro-oesophageal junction and at

approximately 3 cm above the junction, primarily for

the identi®cation of short-segment Barrett's oesopha-

gus.12 Study drug tablets were counted, diary cards

were reviewed, and symptoms and adverse events were

assessed. A heartburn-focused quality of life was also

completed at baseline, week 6 and week 12, comprising

measurements of several divisions: role-physical, diet,

pain, vitality, social, sleep and mental health. Physical

examinations were repeated at the ®nal visit.

Ef®cacy and safety parameters

Ef®cacy was evaluated by comparing the two treatment

groups in terms of reductions in the frequency and

severity of heartburn episodes, antacid consumption,

erosive oesophagitis healing, and global quality of life

scores. Healing and symptom parameters compared

effervescent ranitidine administered twice daily vs.

calcium carbonate antacids taken as needed, and

antacid consumption was monitored to assess the need

for additional medication to relieve heartburn unre-

sponsive to study medications. Healing was de®ned as

the attainment of an oesophageal grade 0 or 1 on the

adapted Hetzel scale by those individuals who were

initially found to have erosive oesophagitis. Safety was

assessed by monitoring adverse events.

Statistical analysis

The sample size was based on the number of subjects

projected for enrolment during a 6-month period

(estimated at 140 evaluable subjects). The enrolment

of 70 patients per comparison group provides at least

80% power to detect a 25% difference between treat-

ment groups at alpha of 0.05.

Demographic characteristics were compared using

Fisher's exact test or the Wilcoxon rank-sum test; the

two treatment groups were compared in terms of the

frequency and severity of daily (daytime, night-time,

and total) heartburn episodes using the Wilcoxon-rank

sum test; erosive oesophagitis healing rates were

compared using a Mantel±Haenszel test; treatment

groups were compared in terms of weekly antacid tablet

consumption using the Wilcoxon-rank sum test;

Fisher's exact test was used to compare the frequency

of adverse events; analysis of variance was used to

assess differences between treatment groups in quality

of life parameters; Fisher's exact test was used to

compare global quality of life scores between treat-

ments.

RESULTS

Subject characteristics

Of the 178 subjects screened for the study, 155 met the

entry criteria and were subsequently randomized to

treatment. The 23 subjects who did not meet entry

criteria had insuf®cient heartburn at baseline or had

confounding upper gastrointestinal disease, including

ulcer disease, Barrett's oesophagus with dysplasia or

cancer (one each), or diffuse oesophageal spasm.

There were no signi®cant differences in demographic

characteristics between the randomized treatment

groups (Table 1). There were also no differences

between randomized treatment groups in heartburn

severity or frequency during the baseline run-in phase,

or baseline oesophagitis grade (Table 2). The numbers

of subjects who withdrew from the study were similar

for the ranitidine group (2 out of 77, 3%) and the

EFFERVESCENT RANITIDINE RELIEVES HEARTBURN 913


antacid group (4 out of 78, 5%; P � 0.68) and study

drug compliance was also similar between the treat-

ment groups. The reasons for study withdrawal were

not due to adverse events and included withdrawal of

consent. One patient developed a duodenal ulcer on

antacids and was withdrawn from study participation.

Relief of heartburn

Daily heartburn frequency and severity scores were

analysed for days 1 through 14 of treatment. The

frequency (Figure 1) and average severity (Figure 2) of

heartburn episodes were signi®cantly less (P £ 0.015)

within 1 day of receiving study medication in subjects

treated with ranitidine, compared to subjects treated

with antacids, and these differences continued through-

out the study period with only sporadic variations.

Grade of oesophagitis did not correlate with response to

treatment (i.e. individuals with non-erosive and erosive

oesophagitis had similar symptom relief patterns).

Antacid consumption

Mean weekly rescue antacid consumption was signi®-

cantly less by week 6 in subjects treated with ranitidine

compared to calcium carbonate antacids. These

differences continued through week 12 (P < 0.001,

Figure 3).

Table 1. Patient characteristics

Calcium carbonate

750 mg as-needed

(n = 78)

Effervescent

Ranitidine

150 mg b.d.

(n = 77)

Sex, n (%)

Female 39 (50%) 34 (44%)

Male 39 (50%) 43 (56%)

Age (years)

Mean (S.E.M.) 41.9 (1.3) 43.4 (1.4)

Range 22.0±72.0 22.0±71.0

Ethnic origin, n (%)

White 64 (82%) 65 (84%)

Black 7 (9%) 5 (6%)

Hispanic 5 (6%) 6 (8%)

Other 2 (3%) 1 (1%)

Height (inches) (n = 78) (n = 76)

Mean (S.E.M.) 66.9 (0.4) 67.7 (0.5)

Range 59.0±77.0 58.0±77.0

Weight (pounds) (n = 78) (n = 76)

Mean (S.E.M.) 181.6 (4.2) 189.7 (4.7)

Range 112.0±265.0 117.0±314.0

Average alcohol intake, n (%)

Non-user 41 (53%) 35 (45%

<1 drink/day 32 (41%) 32 (42%)

1±2 drinks/day 5 (6%) 9 (12%)

>2 drinks/day 0 1 (1%)

Daily tobacco user, n (%) 19 (24%) 19 (25%)

Daily caffeine user, n (%) 67 (86%) 69 (90%)

Table 2. Baseline oesophagitis grade

Calcium carbonate

750 mg as-needed

(n = 78)

Effervescent Ranitidine

150 mg b.d.

(n = 77)

Grade 0 29 (37%) 17 (22%)

Grade 1 14 (18%) 22 (29%)

Grade 2 21 (27%) 27 (35%)

Grade 3 12 (15%) 8 (10%)

Grade 4 2 (3%) 3 (4%)

Figure 1. Heartburn frequency dur-

ing week 1 of treatment (mean

number of episodes per day);

*P < 0.05.



Healing of erosive oesophagitis/Barrett's oesophagus

Seventy-three of the 155 randomized subjects (47%)

had erosive oesophagitis at the baseline endoscopy

(grade 2 or greater). Out of 38 subjects, 21 (55%) with

erosive oesophagitis at baseline, receiving 12 weeks of

ranitidine were healed (grade 1 or less). This was

statistically superior to 29% of patients with erosive

oesophagitis (10 out of 35) who were healed while

taking study antacids (P � 0.022). Nine out of 38

subjects (24%) treated with ranitidine were healed by

week 6, compared to six out of 35 subjects on antacids

(17%), but this difference did not reach statistical

signi®cance (Table 3). Baseline, week 6 and week 12

histological ®ndings did not differ between treatment

groups (P > 0.05).

Quality of life

Subjects in both treatment groups showed numerical

improvements in quality of life scores from baseline to

week 6 (Figure 4), and week 12 (Figure 5). Subjects

receiving ranitidine showed statistically signi®cant

improvements from baseline in vitality (P � 0.026)

and pain scores (P � 0.002) by week 6, and pain by

week 12 (P � 0.002) compared to the antacid group.

Safety

Both study drugs were well-tolerated. There were no

signi®cant differences in the overall incidence of adverse

events, judged by investigators to be potentially related

to study drugs: 12% in the antacid group and 5% in

Figure 2. Average heartburn severity

during week 1 of treatment (mean

daily severity score); *P < 0.05.

Figure 3. Weekly antacid consumption

(mean number of tablets per week of

study antacids or placebo antacids);

*P < 0.05.



the effervescent ranitidine group (P � 0.25). The most

frequently reported adverse events were related to: (i)

the gastrointestinal system (diarrhoea, nausea and

vomiting, positive occult blood, gas, oesophageal spasm,

dyspepsia, constipation, faecal incontinence and duode-

nal ulcer; 12% in the antacid treatment group and 3%

in the ranitidine group; P � 0.056); and (ii) the central

nervous system (headache, dizziness, insomnia, malaise,

fatigue, weakness, chills, nervousness; 1% in the

antacid treatment group and 4% in the ranitidine

group; P � 0.37). One subject was withdrawn from the

trial due to development of a duodenal ulcer while

randomized to antacids.

DISCUSSION

Effervescent ranitidine 150 mg tablets administered

twice daily for 12 weeks were signi®cantly more

effective in reducing the frequency and severity of

heartburn episodes compared with as-needed 750 mg

calcium carbonate antacids. Signi®cant (P £ 0.015)

reductions in heartburn frequency and severity were

observed within 1 day of initiating treatment with

effervescent ranitidine compared to calcium carbonate

antacids. In subjects with erosive oesophagitis at

baseline, 12-week healing rates were also signi®cantly

(P � 0.022) higher with effervescent ranitidine (55%)

vs. calcium carbonate antacids (29%). Both treatments

were well-tolerated and had similar adverse event

pro®les.

The improvements in heartburn frequency and sever-

ity demonstrated with effervescent ranitidine tablets in

this trial are similar to those of a much larger double-

blind placebo-controlled trial in 438 subjects with

frequent heartburn. In that trial, both effervescent and

standard ranitidine tablets administered twice daily

were shown to be safe and clinically equivalent in

providing heartburn relief in GERD.13 Our study adds

evidence for a signi®cant healing effect for effervescent

ranitidine, along with enhancements in quality of life

parameters.

The effervescent ranitidine tablets used in the present

trial are bioequivalent to other oral ranitidine products.

The dosage regimen was based on the twice daily dosing

Table 3. Oesophagitis healing in subjects with erosive oesopha-

gitis at baseline

Time interval

Calcium

carbonate

750 mg

as-needed

Effervescent

ranitidine

150 mg b.d. P-value

Subjects 35 38

Week 0±6 6/35 (17%) 9/38 (24%) 0.49

Grade 2 5/21 (24%) 8/27 (30%)

Grade 3 1/12 (8%) 1/8 (13%)

Grade 4 0/2 0/3

Week 6±12 10/35 (29%) 21/38 (55%) 0.022

Grade 2 6/21 (29%) 15/27 (56%)

Grade 3 4/12 (33%) 5/8 (63%)

Grade 4 0/2 1/3 (33%)

Figure 4. Mean change from base-

line heartburn-speci®c quality of life

scoresÐweek 6; *P < 0.05.



of standard ranitidine 150 mg tablets that has been

shown to signi®cantly reduce oesophageal acid contact

time and which has been FDA-approved for the

treatment of symptomatic GERD.14 The ®ndings of the

present trial are consistent with those of earlier

randomized, double-blind, placebo-controlled studies of

standard ranitidine 150 mg tablets twice daily for

6 weeks that showed signi®cant ef®cacy for heartburn

relief in patients with mild-to-moderate re¯ux dis-

ease.15±20 The present study also con®rms earlier trials

demonstrating that a regimen of ranitidine 150 mg b.d.

promoted healing of erosive oesophagitis, especially in

patients with mild to moderate erosive GERD. This

serves as a reminder that H2-RAs may be quite effective

for a diagnosis that is now largely treated with proton

pump inhibitors.

In our study, < 20% of subjects had severe erosive

oesophagitis. Like the majority of subjects in other

studies who sought medical attention for GERD, the

majority of subjects in the present population of over-the-

counter antacid users had either normal oesophageal

mucosa or only mild oesophagitis (Hetzel grade 2).21±25

Because the twice daily dosing regimen of effervescent

ranitidine 150 mg tablets provides symptomatic relief of

heartburn, this regimen may be quite satisfactory for

many heartburn sufferers who do not attain adequate

symptom relief with current over-the-counter antacids.

Endoscopic diagnosis of Barrett's oesophagus was

initially made in 6% of study participants; however,

histological con®rmation of unequivocal specialized

columnar epithelium was variable (0±8%) at the

various endoscopic assessments, possibly due to vari-

ations in biopsy site and sample sizes. This suggests that

the diagnosis for both classical and short segment

Barrett's oesophagus can be elusive.

Based on these ®ndings, we conclude that effervescent

ranitidine 150 mg tablets taken twice daily for up to

12 weeks provide safe and effective symptomatic relief

of heartburn in subjects who regularly use antacids.

Ranitidine effervescent tablets may offer the added

advantage of ef®cacy in healing mucosal lesions in

those heartburn sufferers who do have erosive oeso-

phagitis. Because of the apparent comparability of

standard ranitidine tablets and effervescent ranitidine

tablets, in terms of safety and ef®cacy, effervescent tablets

may also provide an alternative to standard tablets for

subjects who prefer this dosage form.

Finally, results of this study support the use of

ranitidine 150 mg b.d. as empirical therapy for patients

with chronic frequent heartburn. Refractory symptoms

still warrant endoscopic evaluation to detect the

approximately 20±30% who may have more severe

erosive disease, or the smaller but important group who

may have Barrett's oesophagus and may require inter-

mittent monitoring to exclude dysplasia and cancer.

ACKNOWLEDGEMENTS

This study was supported by an unrestricted education-

al grant from GlaxoWellcome.

Figure 5. Mean change from baseline

heartburn-speci®c quality of life scor-

esÐweek 12; *P < 0.05.



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managing heartburn at the ‘base’ of the gerd ‘iceberg’: effervescent ranitidine 150 mg b.d....

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