Treatment of erosive reflux esophagitis resistant to H2-receptor antagonist therapy

Digestive Diseases and Sciences, Vol. 40~ No. 3 (March 1995). pp. 590-597

Treatment of Erosive Reflux Esophagitis Resistant to H2-Receptor Antagonist

Therapy Lansoprazole, a New Proton Pump Inhibitor

MALCOLM ROBINSON, MD, DONALD R. CAMPBELL, MD, STEPHEN SONTAG, MD, and SEYMOUR M. SABESIN, MD

Fifty-four patients with endoscopically documented therapy-resistant erosive reflux esophagitis were treated with lansoprazole, a new proton pump inhibitor, for up to 12 weeks. Prior to entry, all had remained unhealed after treatment with at least two histaminez-receptor antagonists, at therapeutic doses or higher, for at least 12 weeks. Patients were randomized to receive either 30 or 60 mg lansoprazole once daily. Endoscopy was performed and symptoms assessed at weeks 2, 4, 6, 8, and 12. Fifty-nine percent of the 50 evaluable patients were healed (ie, no evidence of erosions) after only two weeks of lansoprazole. Cumulative endoscopic healing rates were 82% and 92% by week 4 and week 8, respectively, and the two doses were equally effective in healing. The 30- and 60-rag doses effected a decrease in the overall symptom score from 5.30 and 4.85 to 2.35 and 1.67, respectively, by the final treatment visit (P = 0.001). No clinically significant adverse events or changes in laboratory parameters were observed, and no patients withdrew prematurely from the study. This study demonstrates that lansoprazole therapy is highly effective in healing erosive reflux esophagitis resistant to therapy with histamine H2-receptor antagonists.

KEY WORDS: lansoprazole; erosive reflux esophagitis; proton pump inhibitor; acid secretion inhibition.

Although numerous agents have been shown to improve the symptoms associated with reflux esophagitis and to improve the endoscopic appearance of erosive

Manuscript received May 23, 1994; accepted September 29, 1994.

From the Oklahoma Foundation for Digestive Research, De- partment of Medicine, University of Oklahoma College of Medi- cine, Oklahoma City, Oklahoma; University of Kansas School of Medicine and Department of Veterans Affairs Medical Center, Kansas City, Missouri; Veterans Affairs Edward Hines Jr. Hospital, Hines, Illinois; and Rush-Presbyterian St. Luke's Medical Center, Chicago, Illinois.

Supported by a grant from TAP Pharmaceuticals Inc., Deerfield, Illinois.

Address for reprint requests: Dr. Malcolm Robinson, Oklahoma Foundation for Digestive Research, University of Oklahoma Col- lege of Medicine, 711 Stanton L. Young Blvd., Suite 501, Okla- homa City, Oklahoma 73104.

590

esophagitis, complete healing of erosive reflux esophagitis (RE) was difficult to achieve prior to the intro- duction of proton pump inhibitors (1). In placebo- controlled trials, complete healing of esophageal mucosa was documented in approximately 50% of patients receiving 12 weeks of histamine H2-receptor a n t a g o n i s t ( H 2 - R A ) therapy (1). Proton pump inhibitor therapy appears to be much more effective than H2-RA therapy in healing erosive esophagitis, and four-week healing rates of 82-95% have been reported for omeprazole (2, 3).

Lansoprazole, a substituted benzimidazole contain- ing a novel trifluoroethyI group, is a new proton pump inhibitor. It is converted in the acidic environment of the parietal cell canaliculi to active sulfenamide de-

Digestive Diseases and Sciences, Vol. 40, No. 3 (March 1995) 0163-2116/95/0300-059(~$07.50/0 f~.'~ 1995 Plenum Publishing Corporation

LANSOPRAZOLE HEALS RESISTANT EROSIVE RE

rivatives, which bind to the H+,K+-ATPase enzyme system of the par ietal cell canalicular membrane and reduce gastric acid secret ion by selective inhibition of H+,K+-ATPase . Like omeprazole , lansoprazole inhibits both centrally and per ipheral ly media ted gastric acid secret ion (4, 5) in addi t ion to inhibiting the secret ion and actions of pepsin (6).

Previous studies in humans demons t r a t ed that orally adminis tered lansoprazole, in doses between 15 and 60 rag, inhibits basal and st imulated acid secretion in a dose-dependen t fashion. Like o ther proton pump inhibitors, but unlike H2-RAs, a single morning dose of lansoprazole provides effective suppression of gastric acid product ion over 24 hr (7).

In rani t idine-control led trials, lansoprazole 30 or 60 rag/day has been consistently super ior to ranit idine 150 mg twice a day in both healing rates and symptom relief (7). For example, in studies of pat ients with endoscopical ly conf i rmed RE, e ight-week healing rates on lansoprazole 30 mg were about 90% compared to healing rates on ranit idine 150 mg twice daily of about 50 -70% (7). Moreover , in a trial com- paring lansoprazole 30 rag/day with omeprazole 20 mg/day in 229 evaluable RE patients, the healing rates after four and eight weeks were similar (63 and 65% after four weeks and 85 and 87% after eight, respectively) (8).

The results from the first US study of lansoprazole in pa t ien t s with erosive esophagi t i s res is tant to H2-RA therapy are reported. The objective of this prel iminary, dose-ranging study was to assess the efficacy and safety of once-daily adminis trat ion of 30 and 60 mg lansoprazole in patients with resistant erosive esophagitis.

MATERIALS AND METHODS

Study Design. Patients were randomized to receive either 30 mg or 60 mg of lansoprazole as a single daily dose before breakfast for up to eight weeks. Lansoprazole was administered in a double-blind fashion with respect to dose, but not to drug. During the study, patients who demonstrated endoscopically documented healing were considered to have completed the study at that point and received no further treatment, To determine whether extended or additional treatment with lansoprazole 60 rag/day would produce healing in patients who did not heal during eight weeks of blinded therapy, unhealed patients were scheduled to receive an additional four weeks of open-label treatment at the end of the eight-week double-blind period.

Patients were not allowed to take corticosteroids, antico- agulants, or any ulcerogenic medications during treatment, with the exception of one aspirin per day or one NSAID per week. Antiulcer medications were not permitted but patients were given 50 Gelusil tablets at each visit, to be taken

as needed for relief of heartburn and upper abdominal discomfort.

Evaluations were scheduled at two-week intervals for the first eight weeks. Each visit included endoscopic assessment; clinical laboratory evaluations including fasting serum gastrin levels; and evaluations of symptoms, adverse events, and antacid use. Symptoms were further evaluated using diary data recorded by the patients. The diary included information on antacid use, symptoms experienced, and concomitant medications.

The informed consent and protocol were approved by the Institutional Review Board of each center.

Study Group. Patients with resistant erosive esophagitis were enrolled into the study. To be considered resistant to H2-RA therapy, patients had to have symptoms and esophagitis despite having received at least two different H_,-RAs, at standard therapeutic doses or higher, during the 12 weeks immediately preceding study enrollment. Treatment with these agents was permitted up to the first day of the study. (At the time the study was performed, "standard therapeutic doses" were defined as cimetidine 800 rag/day, famotidine 40 mg/day, nizatidine 300 rag/day, and ranitidine 300 mg/day. The doses recommended for RE treatment have since increased for all of these drugs except nizatidine.)

To be enrolled into the study, the patient had to have endoscopic evidence of erosive RE (at least one erosion in the 1-cm area above the squamocolumnar junction of the esophageal and gastric mucosae) within seven days of study entry. The extent and severity of RE was graded on a five-point modified Savary-Miller scale (9). The modified scale (Table 1) was more precise in terms of the size of erosions (ulcerations) and the area of the esophagus af- fected. "Healing" was defined as a return of the esophageal mucosa to grade 0 (ie, no evidence of erosion).

Patients were excluded from participating in the study if they were less than 18 years old or had not given informed consent. In addition, patients were not to have used any potentially ulcerogenic drugs, including NSAIDs or aspirin, chronically within one month prior to the screening endoscopy, or to have received proton pump inhibitors or inves- tigational drugs, including lansoprazole, within 12 weeks.

Study End Points. The primary efficacy variable was the endoscopic assessment (either healed or unhealed) at each time point during treatment. Patients who were healed, as demonstrated endoscopically, at any visit received no further medication and were considered healed at all subse- quent time points. Other efficacy end points included change in four major symptoms of esophagitis (upper abdominal burning, heartburn, day and night abdominal pain) from baseline to the final treatment visit and patient diary recordings of Gelusil use and abdominal pain.

Safety variables included assessments of adverse events, clinical laboratory variables, including gastrin levels, and physical examination, electrocardiogram (ECG), and vital sign data.

Statistical Methods. All statistical analyses were based on two-tailed tests, and significance was determined by a P value of -<0.05. The chance of detecting a significant difference between the 30- and 60-mg treatment groups in the evaluable sample size (50 patients) was 70% if the true healing rates were 65% and 95%, respectively (P = 0.05,

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ROBINSON ET AL

TABLE 1. GRADING SCALE FOR EROSIVE REFLUX ESOPHAGITIS*

Grade Description

0~ 1 2 3 4

No evidence of erosion Solitary erosion in the squamocolumnar junction More than one erosion in the squamocolumnar junction Erosions involving up to 50% of the distal 5 cm of the esophagus Multiple erosions and/or one or more large peptic ulcers >0.5

cm involving >50% of the distal 5 cm of the esophagus

*Modified from Savary and Miller (9). Ulcers were defined as discrete lesions with appreciable depth and >3 mm in diameter. Erosions, or ulcerations, were defined as superficial breaks, <3 mm in diameter and with or without exudate, in the esophageal mucosa; The squamocolumnar junction includes the 1-cm area above the junction of the esophageal and gastric mucosae. The distal 5 cm of the esophagus encompasses a 5-cm area that includes the squamocolumnar junction and above.

tGrade used to define "healing."

2-tailed test). Baseline values were the last values obtained prior to the first dose of study medication. Symptom severity of none, mild (symptom did not last long or was easily tolerated), moderate (symptom caused discomfort and in- terrupted usual activities), and severe (symptom caused great interference with usual activities and may have been incapacitating) was scored as 0, 1, 2, and 3, respectively.

The proportion of patients healed in each dose group was compared at all time points with the Mantel-Haenszel test using 2 x 2 tables. Healing rates were adjusted for each stratification factor and examined using Mantel-Haenszel methods for combining 2 × 2 tables across each factor level. Symptom assessments were analyzed by Cochran-Mantel- Haenszel methods, using baseline values as covariates. Changes in the symptom score sum (combining the four primary symptoms) were compared using analysis of vari- ance (ANOVA). Comparisons of day and night abdominal pain and Gelusil use were made using the Wilcoxon two- sample test.

The proportions of patients experiencing adverse events during treatment (or within three days of the last dose of study medication) were compared between dose groups using Fisher's exact tests. Changes in laboratory values were evaluated both as the percentage change, and as the mean change from baseline to the final treatment visit. Fasting gastrin values were derived from samples obtained after a fast of at least eight hours.

RESULTS

Demographics and Baseline Esophagitis Grade. Fifty-four patients with resistant erosive RE qualified for the study and were enrolled at the four participating centers. Enrollment was balanced across centers. Four of the patients were deemed nonevaluable (three because their prior H2-RA therapy was at lower than the therapeutic dose, one because of start- ing chronic NSAID therapy during treatment). Data from these patients were included in the intent-to- treat efficacy analyses and in all safety analyses. None of the enrolled patients withdrew from the study prematurely for any reason.

Of the 50 evaluable patients, 43 were male and 49 were Caucasian. The patients ranged in age from 25 to 75 years (mean: 53.2). Fourteen (28%) were cigarette smokers, 16 (32%) users of alcohol, and 37 (74%) consumers of caffeine. Ten had a history of duodenal ulcer and three of gastric ulcer. There were no significant differences between dose groups in any of the demographic variables.

Thirty-one (62%) of the 50 evaluable patients had grade 3 or 4 erosive RE at baseline, 14 (28%) had grade 2, and five (10%) had grade i. There were no significant differences between dose groups in the distribution of baseline grade.

Healing Rates. Healing was rapid with cumulative healing rates at two, four, and eight weeks of 59%, 82%, and 92%, respectively. Forty-seven (94%) of the 50 evaluable patients showed healing with up to 12 weeks of lansoprazole treatment (Table 2). There was no significant difference between the two dose groups at any point during the study. The results for the intent-to-treat cohort (54 patients) were similar to those for the evaluable patients, with 56% healed after two weeks, 80% healed after four weeks, and 94% healed after eight weeks.

Of the four patients who remained unhealed after eight weeks (one treated with 30 mg and three treated

TABLE 2. CUMULATIVE NUMBER (%) OF EVALUABLE PATIENTS HEALED, BY DOSE GROUP AND DURATION OF TREATMENT

Lansoprazole N (%) Patients healed at treatment week

dose (IV) 2 4 6 8 12"

30 mg (23) 13 (57) 20 (87) 21 (91) 22 (96) 23 (100) 6 0 m g (27) 16 (62) 20(77) 23 (89) 24 (89) 24 (89) Total (50) 29 (59) 40(82) 44(90) 46 (92) 47 (94)

*Patients not healed by week 8 received open-label 60-mg lansoprazole for an additional four weeks.

592 Digestive Diseases and Sciences, Vol. 40, No. 3 (March 1995)


with 60 mg lansoprazole), all had grade 3 or 4 esophagitis at baseline. The one unhealed patient treated with 30 mg during the double-blind phase healed after the four additional weeks of 60 mg; the remaining three patients demonstrated modest improvement in their endoscopic results after continued therapy. One patient with grade 4 RE at screening improved to grade 3 at the final visit, while a second patient with grade 4 at entry showed a decrease in the ulcer size at the final visit, which was still classified as grade 4. The third patient entered with grade 3 esophagitis and improved to grade 2 after 12 weeks of lansoprazole treatment.

Because there was minimal difference in healing rates between the lansoprazole dosage groups, the efficacy results were combined across dosages to eval- uate the possible influence of gender, age, and risk factors on healing with lansoprazole. Lansoprazole was equally effective in healing resistant erosive RE in men and women, in all age groups, and in users and nonusers of alcohol, tobacco, and caffeine.

The six cigarette smokers who were randomized to 30 mg lansoprazole were healed after four weeks, and all 14 of the cigarette smokers in the study were healed after six weeks of treatment. Among alcohol

users, all nine receiving 60 mg lansoprazole and five of the six receiving 30 mg were healed after six weeks.

Healing rates were similar regardless of the dose of previous H2-RA therapy. Thirty-six of the 50 evaluable patients had been treated with H2-RA doses between 1 and 1.5 times the standard therapeutic doses at the time this study was conducted (the low- dose group); the remaining 14 patients had been treated with doses greater than 1.5 times the therapeutic dose (high-dose group). After eight weeks of lansoprazole therapy, 94% of the patients in the low- dose group and 93% of the high-dose group were healed.

Patients with less severe disease appeared to heal more quickly, although the differences were not statistically significant. After eight weeks, all patients with grade 1 or 2 were healed, compared to 95% of grade 3 patients and 75% of grade 4 patients (Figure 1); this trend was not statistically significant. Thus, even with the predominance of patients with grade 3 or 4 in this study population (31/50; 62%), the overall healing rates at weeks 6, 8, and 12 were 90%, 92%, and 94%, respectively.

Relief of Symptoms. Effective symptom relief was obtained with both doses of lansoprazole. For each

100-

LEGEND _A Grade 1 (n=5)

co- Grade 2 (n=14) [ ~ Grade 3 (n=lg)

Grade 4 (n--12)

,~ 6o.

C.) 40-

20-

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2 4 6 8 l~. ' WEEKS OF TREATMENT

Fig 1. Cumulative healing rates by severity of disease (esophagitis grade) at entry. After eight weeks, all patients with grade 1 or 2 erosive RE were healed, compared to 95% of grade 3 patients and 75% of grade 4 patients. Logistic regression showed no significant difference in healing rates based on baseline esophagitis grade.

Digestive Diseases and Sciences, Vol. 40, No. 3 (March 1995) 593

primary symptom of esophagitis--upper abdominal burning, heartburn, day abdominal pain, and night abdominal pain--at least two thirds of the patients who presented with the symptom had resolution or improvement by the final visit. This improvement was quantified by using an overall symptom score, which evaluated relief of symptoms from baseline to each patient's final treatment visit. Symptom scores for each patient were obtained as the sum of the severity rating for each of the four primary symptoms (see Materials and Methods for severity ratings).

Significant (P = 0.001) symptom relief was obtained by the final treatment visit for both the 30- and 60-mg doses of lansoprazole. For the evaluable cohort, the mean score was reduced from 5.30 to 2.35 in the 30 mg group (N = 23), and from 4.85 to 1.67 in the 60 mg group (N = 27). There were no significant differences between the two dose groups in either the evaluable or intent-to-treat cohort.

When relief of heartburn was assessed separately, lansoprazole effectively relieved heartburn symptoms in both dose groups (Figure 2). At the final visit, only three patients experienced moderate or severe heart-

ROBINSON ET AL

burn. All three had had severe heartburn at baseline and were randomized to the 30-rag group.

Lansoprazole 60 mg produced significantly greater relief of heartburn (P = 0.049) than the 30-mg dose (Figure 2). At the final treatment visit, four patients in the 60-mg group had mild heartburn; the rest reported none. In contrast, as indicated above, six patients in the 30-mg group reported mild heartburn, one reported moderate, and two reported severe.

Patient Diary Results. The reported symptomatic improvement associated with lansoprazole therapy, as evaluated by the investigator, was corroborated by the patient self-reporting of day and night abdominal pain and the limited use of Gelusil for abdominal discomfort as recorded in the patient diaries. Among the lansoprazole 30-mg group, patients reported experiencing abdominal pain an average of between eight and nine days during the eight weeks of the study, which correlated well with the median use of Gelusil of eight days during the study. In comparison, among the 60-mg group, patients reported abdominal pain an average of only two to four days, which also

L~

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BASELINE I00-

90-

80-

70-

80-

50-

40-

30 4

20-

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0 30 m g n=23

FINAL

60 m g 30 m g n=27 n=23

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60 m g n=27

LEGEND None

Mild Modera t e

m l l S e v e r e

*Significantly greater h e a r t b u r n relief w i t h 60 m g t h a n 30 m g

Fig 2. Lansoprazole produced relief of heartburn from baseline to the final treatment visit. Relief in patients in the 60-rag group was significantly superior (P = 0.049) to that observed in patients treated with 30 mg.

594 Digestive Diseases and Sciences, I/'ol. 40, No. 3 (March 1995)


correlated well with the minimal median Gelusil use of only four days during the study.

Safety Assessments. Both doses of lansoprazole were well tolerated. No clinically significant events occurred, and no patient enrolled withdrew prematurely due to adverse events. Headache and diarrhea were the most frequently reported complaints. There were no statistically significant differences between the two dose groups in adverse event reporting rates, although diarrhea was reported more commonly among the 60-mg group (17%) than among the 30-mg group (4%). The incidence of headache was 29% among the 30-rag group and 23% among the 60-mg group.

Laboratory assessments revealed no clinically significant changes in any parameter from baseline to the final treatment visit in either dose group. Fasting serum gastrin levels remained within the normal range (0-100 pg/ml) for most patients during treatment. Of the 35 patients with fasting gastrin values obtained at baseline and during treatment, six had gastrin values above 100 pg/ml at the final treatment

visit (Figure 3). Of these six, two had baseline values above 100 pg/ml and four had baseline values within the normal range. The median increases in fasting serum gastrin levels from baseline to final treatment visit, by dose group, were 47% for the 30-mg group and 77% for the 60-mg group. This difference was not statistically significant. The median serum levels at baseline and at final visit were 41 and 58 pg/ml, respectively, for the 30-mg group, and 36 and 63 pg/ml, respectively, for the 60-mg group.

DISCUSSION

This pilot study was the first US trial of lansoprazole in patients with reflux esophagitis, resistant to H_~-RA therapy. The study demonstrates that tanso- prazole is a very effective therapy for healing erosive esophagitis and for controlling the symptoms associated with it. The eight-week healing rate of 92% is comparable to eight- and 12-week (85-90%) healing rates reported from omeprazole studies (10, 11) of

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.c_ 20000 L=

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100

400-

300.

200-

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! ! ! I Baseline Final Visit Baseline Final Visit

Lansoprazole 30 mg Lansopr~u~ole 60 mg

Fig 3. Change in individual serum gastrin levels from baseline to final visit on lansoprazole treatment.

Digestive Diseases and Sciences, Vol. 40, No. 3 (March 1995) 595

patients resistant to H 2 - R A therapy, which utilized the higher 40-rag dose of omeprazole.

Lansoprazole was highly and rapidly effective in healing erosive esophagitis across all grades of disease severity and across all demographic and risk factor variables. Although the differences were not statistically significant, there was an apparent ten- dency toward slower healing as severity of esophagitis increased. In contrast to results reported in other studies (12), in which healing rates were slightly reduced for cigarette smokers, all 14 of the cigarette smokers in the study were healed after six weeks of treatment. Among alcohol users, 14 of 15 were healed after six weeks.

Since the patients who participated in the study were receiving H2-RA therapy and had persistent disease, a placebo was not included in the study design. The selection of doses for this trial was based on several factors, including the need for marked and prolonged acid suppression to treat resistant esophagitis (1, 10), and the effective dose-range of lansoprazole. Recent research indicates that in a significant percentage of patients with resistant esophagitis, basal acid output (BAO) is elevated in the hyperse- cretory range (13). Collen et al (13) found that pretreatment BAO was significantly higher among the 12 esophagitis patients who did not respond to ranitidine 300 mg twice a day compared to the 11 patients who did. Moreover, they demonstrated a significant asso- ciation between the pretreatment BAO and the daily dose of ranitidine that patients needed to become free of symptoms. There was also a significant asso- ciation between the presence of gastric acid hyperse- cretion (defined as BAO > 10 meq/hr) and the need for doses of ranitidine above 300 mg daily to achieve symptom control.

The need for greater acid suppression to treat reflux esophagitis is supported further by metaanalysis of healing rates in esophagitis (14), The results demonstrated that maintenance of intraesophageal pH above 4 was the single most important factor in determining healing rates. These results could explain the failure of standard doses of ranitidine to produce complete esophageal healing (1) and the effectiveness of omeprazole 40 mg in healing erosive esophagitis unresponsive or refractory to H 2 - R A therapy (10, 11). These studies (10, 11) evaluating omeprazole in patients with resistant RE utilized at least 40 mg/day of omeprazole rather than the standard dose of 20 mg/day.

Lansoprazole, in doses of 30 mg or 60 mg once daily, has been shown to be more effective than rani-

ROBINSON ET AL

tidine in healing esophagitis (7). Based upon gastric pH data from pharmacodynamic studies (unpub- lished data on file, TAP Pharmaceuticals), it was expected that the higher dose would produce superior endoscopic healing among patients unresponsive to He-RA therapy. Therefore, understanding the need for greater acid suppression to treat resistant RE effectively, 30 mg and 60 mg of lansoprazole were evaluated in this pilot study.

The efficacy results from this study indicate that there is no significant difference in healing rates between the two doses. The lack of a dose-response relationship for healing rates might be explained, considering the results of the metaanalysis above (14), if the 30-rag dose is able to suppress gastric acid sufficiently to maintain the pH above 4 for most of the 24-hr dosing interval. Gastric pH data from a study in normal volunteers do support this hypothesis (unpub- lished data on file, TAP Pharmaceuticals). In this study, Iansoprazole 30 rag, administered to 14 healthy volunteers, maintained the gastric pH above 4 for an average of 66% of a 24-hr period (baseline average was 11%), compared to 51% for omeprazole 20 mg (baseline average was 13%), administered to the same volunteers.

Given the fact that 22 of 23 evaluable patients treated with the 30-rag dose were healed after eight weeks of treatment, 30 mg/day appears to be the appropriate dose of lansoprazole for the majority of patients with erosive esophagitis. Although the change in gastrin levels was not significantly different between the two doses, the median increase was 47% for the 30-mg group compared to 77% for the 60-mg group, and a dose-response relationship for gastrin level increases was found over the range of 15 to 60 mg/day in one study (15). These results suggest that 30 mg is the preferred dose of lansoprazole for most patients with resistant reflux esophagitis.

In summary, lansoprazole once daily has been shown to be highly effective therapy in the treatment of erosive esophagitis resistant to standard treatment with H2-receptor antagonists. Lansoprazole 30 mg was as effective as 60 rag, resulted in 94% healing after eight weeks of therapy, and was well tolerated.

REFERENCES

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Gibson GG, Grant AK, Shearman DJC, Whitehead R, Buckle PJ: Healing and relapse of severe peptic oesophagitis after treatment with omeprazole. Gastroenterology 95:903-912, 1988

3. Sontag S J, Hirschowitz BI, Holt S, Robinson MG, Behar J, Berenson MM, McCullough A, Ippoliti AF, Richter JE, Ahtaridis G, McCallum RW, Pambianco DH, Vlahcevic RZ, Johnson DA, Collen MJ. Lyon DT, Humphries TH, Cagliola A, Bcrman RS: Two doses of omeprazole versus placebo in symptomatic erosive esophagitis. The U.S. Multicenter Study. Gastroenterology 102:109-118, 1992

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6. Matsuo Y, Takemoto T, Miwa T, Iwasaki A, Asaoka A: Clin- ical study of the inhibitory effect of AG-1749, a proton pump inhibitor, on nocturnal gastric acid secretion: Evahmtion of dosage and administration stage. Yakuri to Chiryo t8:4865- 4876, 1990

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Ekstrom P: Lansoprazole vs omeprazole in short-term treatment of reflux esophagitis. Results of a Scandinavian multicen- tre trial. Gastroenterology I02:A80, 1992 (abstract)

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1(/. Klinkenberg-Knol EC, Jansen JBMJ, Lamers CBWH, Nelis F, Snell P, Meuwissen SG: Use of omeprazole in the management of reflux oesophagitis resistant to Hz-receptor antagonists. Scand J Gastroenterol 24(suppl 166):88-93, 1989

11. Lundell L, Backman L, Ekstrom P, Enander LH, Fausa O, Lind T, Lonroth H, Sandmark S, Sandzen B, Unge P, Westin IH: Omeprazole or high-dose ranitidine in the treatment of patients with reflux oesophagitis not responding to 'standard doses' of H~-receptor antagonists. Aliment Pharmacol Ther 4:145-55, 1990

12. Bardhan KD, Long R, Hawkey C J, Wormsley KG, Brocklc- bank D, Moules I: Lansoprazole, a new proton-pump inhibitor, vs ranitidine in the treatment of reflux erosive esophagitis. Gastroenterology 100:A30, 1991 (abstract)

13. Collen M J, Lewis JH, Benjamin SB: Gastric acid hypersecre- tion in refractory gastroesophageal reflux disease. Gastroen- terology 98:654-661, 1990

14. Bell NJV, Burger DL, Howden CW, Wilkinson J, Hunt RH: Appropriate acid suppression for the management of gas- tro-oesophageal reflux disease. Digestion 51(suppl 1):59-67, 1992

15. Muller P, Drammann HG, Leucht U, Simon B: Human gastric acid secretion following repeated doses of AG-1749. Aliment Pharmacol Ther 3:193-198, 1989

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Treatment of erosive reflux esophagitis resistant to H2-receptor antagonist therapy

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