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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References

Background : Many individuals with acid-related gastrointestinal disorders have difficulty in swallowing oral agents.

Aim : To compare the bio-availability of a single dose of lansoprazole orally disintegrating tablet with that of an intact capsule.

Methods : One hundred and twenty healthy subjects participated in two prospective, Phase I, open-label, two-period cross-over studies to receive lansoprazole, 15 mg or 30 mg. Within each study, subjects were randomized into two parallel cohorts consisting of 30 subjects per regimen, dispensed in opposing sequence over two periods separated by a 7-day washout period. Blood samples were collected on day 1 of both periods to determine the pharmacokinetic parameters.

Results : Tmax occurred at 1.8 and 2.0 h with the 15-mg and 30-mg tablets, respectively. Dose proportional increases in Cmax, AUCt and AUC were observed in the 15-mg and 30-mg groups. The terminal elimination half-lives (t1/2) were identical in both dose groups (1.18 h). Lansoprazole administered as the orally disintegrating tablet was bio-equivalent to the intact capsule formulation with respect to Cmax, AUCt and AUC.

Conclusions : Lansoprazole orally disintegrating tablets, 15 mg and 30 mg, are bio-equivalent to the respective dose administered as the intact capsule. This novel dosage formulation represents an option for patients who have difficulty in swallowing oral agents.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References

Since their release approximately a decade ago, numerous studies have confirmed the greater clinical efficacy of the proton pump inhibitor class of antisecretory agents, particularly when compared with histamine-2 receptor antagonists.1–8 Whilst the proton pump inhibitors omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole clearly represent the optimal therapeutic strategy, a percentage of clinical situations exist in which patients are unable to or should not be given a solid oral dosage formulation.

A substantial number of studies have confirmed that opening the lansoprazole or omeprazole capsule and administering the enteric-coated granules in a small amount of soft food (e.g. apple sauce, pudding, yoghurt), mixing the granules with water or fruit juices (e.g. apple or orange), or preparing a sodium bicarbonate-based suspension prior to administration orally or via a nasogastric, jejunal or feeding tube is bio-equivalent (i.e. similar pharmacokinetic parameters) to the administration of the intact capsule, and produces an equivalent pharmacodynamic response (i.e. degree of acid suppression/increase in intragastric pH).9–17 In addition, recent evidence has suggested that the administration of 30 mg of lansoprazole granules as a sodium bicarbonate suspension, or suspended in apple juice, via a nasogastric tube produces significantly greater pharmacodynamic effects (greater mean 24-h pH values and higher percentages of time pH > 4) than the administration of intravenous pantoprazole, 40 mg, to healthy subjects,18, 19 or continuous intravenous ranitidine at a dose of 6.25 mg/h to mechanically ventilated intensive care unit patients.20

These bio-equivalence and pharmacodynamic studies performed with the oral administration of lansoprazole granules confirm the clinical utility of these dosage formulations. However, clinical (as well as social) situations exist in which patients are unable to or do not want to administer a formulation that requires co-administration of a liquid or soft food. A proton pump inhibitor that could be administered to or by these individuals as a convenient and discrete dosage formulation would be highly desirable.

Two prospective, open-label, single-centre, randomized, cross-over studies were designed to investigate and compare the pharmacokinetics and bio-equivalence of a novel orally disintegrating tablet formulation of lansoprazole, 15 mg and 30 mg, with those of the same dose administered as an intact capsule. As the design of the studies was identical and the pharmacokinetic and bio-equivalence results were consistent, the data from the two studies were pooled.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References

One hundred and twenty healthy male and non-pregnant, non-lactating female subjects, 18–55 years of age, who had abstained from nicotine products for at least 6 months before the study began, were enrolled in and completed one of two Phase I, single-dose, randomized, open-label, two-period cross-over, single-centre studies. Eligible subjects weighed within 15% of the acceptable range, according to the 1983 Metropolitan Life Insurance Company's tables for height and weight.21 The medical history and physical examination, 12-lead electrocardiography, vital sign measurements, routine evaluations of haematology and chemistry laboratory values and urinalysis yielded no evidence of clinically significant medical conditions. Subjects were not to take any prescription or non-prescription medications (with the exception of the continuation of oral contraceptives or hormonal replacement therapy) within the 2 weeks before administration of the study drug or during the course of the study. Each subject signed an informed consent form before participating in the study. The procedures followed were in accordance with the ethical standards of the institution's committee on human experimentation.

Study design

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References

Subjects enrolled in each study were randomly assigned in a 1 : 1 : 1 : 1 ratio to one of four groups that were split into two parallel cohorts (cohorts 1 and 2). Subjects in the first study received an equal amount of drug (lansoprazole 15 mg), dosed in two regimens (one orally disintegrating tablet, one capsule) and administered over two periods (periods 1 and 2) in an opposing sequence of cross-over regimens (sequence AB or BA). Subjects in the second study received lansoprazole 30 mg, dosed in two regimens (one orally disintegrating tablet, one capsule) and administered over two periods (periods 1 and 2) in an opposing sequence of cross-over regimens (sequence AB or BA). In each study, the cross-over regimens were separated by a washout interval of 7 days and, on completion of each study, all enrolled subjects had received both regimens of study drug. A 7-day washout period was considered to be adequate based on the short (1.5 h) half-life of lansoprazole.

Subjects were confined to the clinical research unit for approximately 28 h in period 1 and for approximately 40 h in period 2. The extended confinement in period 2 was required so that post-study laboratory evaluations could be completed after approximately 10 h of fasting. Subjects were admitted to the research unit on the evening before dosing and were served dinner (18.00 h) and a snack (21.00 h) before beginning a 10-h fast (approximately 22.00 h). On each dosing day, the lansoprazole regimens were administered at approximately 08.00 h. No food or beverages were allowed, except water to quench the thirst, for at least 4 h following drug administration. During periods 1 and 2, lunch was served at approximately 12.00 h (following 4-h blood collection) and dinner was served at approximately 18.00 h (following 10-h blood collection). All subjects received the same standardized meals in the same sequence. Grapefruit or grapefruit-containing products and xanthine- or caffeine-containing foods and beverages were prohibited during the study periods because these foods contain compounds that may affect cytochrome P450-metabolizing enzymes either by induction or inhibition.

On day 1 of period 1, in both studies, subjects were administered one 15-mg or 30-mg lansoprazole orally disintegrating tablet that was placed directly on the tongue and allowed to disintegrate completely without the subject chewing or swallowing the tablet, or one 15-mg or 30-mg lansoprazole capsule swallowed intact with 180 mL of water. Study regimens were timed by the investigator using a stopwatch and subjects were instructed to notify the clinical staff when the lansoprazole orally disintegrating tablet had completely disintegrated. A hand and mouth check was performed to confirm that the tablet had completely disintegrated or the capsule had been swallowed. Subjects were instructed to remain in a supine position for at least 2 h after administration of each dose. On day 1 of period 2, subjects in each respective study were administered the cross-over drug formulation in the sequence.

Safety evaluations were conducted by the monitoring of vital signs, including sitting blood pressure, pulse, respiratory rate and oral temperature, and laboratory evaluations. The investigator monitored all subjects for the occurrence of any adverse event. The severity of all events and the possible relationship to the study drug were assessed. Severity was defined as mild if the adverse event was transient and easily tolerated, moderate if the subject had discomfort and interruption of normal activities, or severe if considerable interference with normal activities occurred, or if the event was incapacitating or life threatening. In addition, the relationship between adverse events and the study drug was characterized as definite, probably, possible or non-existent.

Pharmacokinetic blood sample collection and analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References

Blood samples used for the determination of plasma lansoprazole concentrations were collected from each subject on day 1 of each cross-over period. Seven-millilitre blood samples were collected by venepuncture into appropriately labelled heparinized tubes (Vacutainer, Becton Dickinson and Company, Franklin Lakes, NJ, USA) at hour 0 (immediately before dosing at 08.00 h) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 and 12 h after dosing, defined as swallowing the intact capsule or placing the tablet on the tongue, in each period. The blood samples were immediately placed on ice and centrifuged, using a refrigerated centrifuge (between 2 and 8 °C), for 15 min at 2500 r.p.m. within 60 min of collection. The plasma samples were transferred into labelled screw-capped polypropylene tubes and frozen at − 20 °C or lower until shipment to MDS Pharma Services (Lincoln, NE, USA) for analysis.

Plasma samples were analysed in a blind manner with regard to regimen using a validated liquid chromatography method with tandem mass spectrometric detection. The lower limit of quantification for lansoprazole was 5.00 ng/mL using a 0.5-mL plasma sample.

Pharmacokinetic and statistical analyses

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References

The sample size calculation was based on the assumption that complete data from 52 subjects, 26 per sequence group, would provide at least 90% power for achieving the equivalence claim with respect to the area under the plasma concentration–time curve (AUC) and maximum observed plasma concentration (Cmax) if the central values differed by 5%. A study size of 60 (30 for each sequence) was chosen to allow for potential drop-outs. Power calculations were performed for logarithmically transformed data, and a central value for a regimen was the exponentiation of the mean for the logarithm. The variances for the logarithm of AUC and the logarithm of Cmax were assumed to be 0.032 and 0.086, respectively, based on data from a pilot study.

Pharmacokinetic values for lansoprazole were estimated by non-compartmental methods using WinNoulin V.3.1 (Pharsight Corporation, Mountain View, CA, USA). Cmax and the time to the maximum observed concentration (Tmax) were taken directly from the plasma concentration–time data. The value of the elimination rate constant (λz) was obtained from the slope of a least-squares linear regression of the logarithms of the plasma concentration–time data from the terminal log-linear phase of the profile. The terminal elimination half-life (t1/2) was calculated as ln(2)/λz. The area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUCt) was calculated by the linear trapezoidal method. The area under the plasma concentration–time curve from time zero was extrapolated to infinity (AUCext) by dividing the last measurable plasma concentration (Ct) by λz. The area under the plasma concentration–time curve from time zero to infinity (AUC) was the sum of AUCt and AUCext.

Analysis of variance (anova), with fixed effects for sequence, cohort, sequence by cohort interaction, period, regimen, period by cohort interaction and regimen by cohort interaction, with a random effect for subject nested within the sequence by cohort combination, was performed for Tmax, λz and the natural logarithms of Cmax, AUCt and AUC. The dosage regimens (lansoprazole 15-mg orally disintegrating tablet vs. lansoprazole 15-mg capsule and lansoprazole 30-mg orally disintegrating tablet vs. lansoprazole 30-mg capsule) were compared at a significance level of 0.05. The relative bio-availability of the orally disintegrating tablet regimen compared with the same dosage administered as the intact capsule was assessed by two one-sided tests,22 with 90% confidence intervals obtained from the analyses of the natural logarithms of Cmax, AUCt and AUC. Bio-equivalence was concluded if the 90% confidence intervals between the orally disintegrating tablet regimen and the same dose administered as the intact capsule were within the 0.80–1.25 range.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References

All 120 subjects completed dosing with one lansoprazole 15-mg orally disintegrating tablet and one intact 15-mg capsule or one lansoprazole 30-mg orally disintegrating tablet and one intact 30-mg capsule. Three subjects with minor entrance criteria deviations not considered to be clinically significant (two with a body weight that exceeded the upper limit by 2.6 kg and 3.2 kg, respectively, and one who was enrolled without a screening pregnancy test) were allowed to participate in the lansoprazole 15 mg study. No subjects were prematurely discontinued from the study due to protocol deviations. One subject (a 23-year-old female) initiated oral contraceptive therapy without the specific approval of the investigator, 1 day after period 1 dosing. Although she was permitted to participate in period 2 of the study, this was nevertheless a protocol violation and she was excluded from the pharmacokinetic analysis.

Subjects enrolled in both studies were similar with respect to demographic characteristics (Table 1). As required by the protocol, all subjects were non-smokers.

Table 1.  Demographic characteristics of subjects enrolled in lansoprazole 15-mg and lansoprazole 30-mg orally disintegrating tablet vs. intact capsule studies
CharacteristicLansoprazole 15 mg (n = 60)Lansoprazole 30 mg (n = 60)
  1. s.d., standard deviation.

Age (mean ± s.d.) (years)36.1 ± 9.136.3 ± 9.7
Gender
 Female27 (45%)28 (47%)
 Male33 (55%)32 (53%)
Race
 Caucasian7 (12%)3 (5%)
 Caucasian/Hispanic47 (78%)51 (85%)
 Black3 (5%)0 (0%)
 Black/Hispanic3 (5%)3 (5%)
 Other/non-Hispanic0 (0%)3 (5%)
Weight (mean ± s.d.) (kg)74.3 ± 11.071.9 ± 11.5
Height (mean ± s.d.) (cm)166.9 ± 8.1164.4 ± 9.3

The majority (82% with lansoprazole 15 mg and 75% with lansoprazole 30 mg) of the subjects in each study experienced disintegration of the orally disintegrating tablet within 60 s. Of those administered the lansoprazole 15-mg orally disintegrating tablet, the tablet disintegration times ranged from 27 s to 2 min 5 s, with a mean of 48 s. Of those administered the lansoprazole 30-mg orally disintegrating tablet, the tablet disintegration times ranged from 21 s to 2 min 18 s, with a mean of 53 s. The strawberry-flavoured tablets appeared to be palatable and were well tolerated by all subjects.

The mean pharmacokinetic values of lansoprazole, 15 mg or 30 mg, after its administration as the orally disintegrating tablet or as an intact oral capsule are summarized in Table 2. The test statistics for the fixed effects for cohort, sequence, cohort by sequence interaction, period, cohort by regimen interaction and cohort by period interaction were not statistically significant for any of the between-lansoprazole-formulation-tested pharmacokinetic parameters, with the exception of period and sequence effects for λz in the lansoprazole 15 mg study, and the period effect for λz and the sequence effects for Tmax and Cmax in the lansoprazole 30 mg study. The 90% confidence intervals for evaluating the bio-equivalence and the corresponding point estimates of the relative bio-availability are summarized in Table 2. Lansoprazole, 15 mg and 30 mg, administered as the orally disintegrating tablet was bio-equivalent to the equivalent dose administered as an intact capsule with respect to Cmax, AUCt and AUC, with the 90% confidence intervals contained entirely within the range 0.80–1.25.

Table 2.  Lansoprazole, 15 mg and 30 mg, pharmacokinetic parameters (mean ± s.d.) by dosage formulation
Pharmacokinetic parameterLansoprazole 15 mgLansoprazole 30 mg
Orally disintegrating tabletIntact capsuleOrally disintegrating tabletIntact capsule
  • AUCt , area under the plasma concentration–time curve from time zero to the time of the last measurable concentration; AUC , area under the plasma concentration–time curve from time zero to infinity; Cmax , maximum observed plasma concentration; Tmax , time to maximum observed concentration; t1/2 , terminal elimination half-life; s.d., standard deviation.

  • Harmonic mean ± pseudo-standard deviation.

  • †  Evaluations of t1/2 were based on statistical tests for the elimination rate constant ( λz ).

  • ‡ 

    Point estimate (90% confidence interval).

No. of subjects60605959
Tmax (h) 1.8 ± 1.01.9 ± 0.92.0 ± 1.12.0 ± 1.0
Cmax (ng/mL) 470.9 ± 182.5486.5 ± 257.81087 ± 470.3997.2 ± 361.5
AUCt (ng.h/mL) 1079 ± 492.51175 ± 913.52551 ± 14252539 ± 1181
AUC (ng.h/mL) 1108 ± 526.41235 ± 11232597 ± 15002583 ± 1233
t1/2 (h) *1.18 ± 0.361.18 ± 0.371.18 ± 0.341.17 ± 0.37
Relative bio-availability    
CmaxAUCt1.059 (0.909–1.235) 1.042 (0.932–1.164) 1.089 (0.958–1.238) 0.992 (0.900–1.092) 
AUC1.033 (0.928–1.150) 0.998 (0.900–1.083) 

The mean concentration vs. time profiles for the lansoprazole 15-mg and 30-mg fast disintegrating tablets, compared with those of the same dose administered as intact capsules, are illustrated in Figures 1 and 2.

image

Figure 1. Mean lansoprazole plasma concentration–time profiles (linear scale). n  = 60 for regimens A and B. LODT, lansoprazole orally disintegrating tablet.

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image

Figure 2. Mean lansoprazole plasma concentration–time profiles (linear scale). n  = 59 for regimens A and B. LODT, lansoprazole orally disintegrating tablet.

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The frequency of adverse events during the treatment period was similar between the orally disintegrating tablet and intact capsule regimens. All adverse events were mild to moderate in severity and none of the events were judged by the investigator to be related to the study drug. In the study involving lansoprazole 15 mg, the incidence of adverse events was 8% with the orally disintegrating tablet (five subjects: four reported headache, two reported nausea and one reported epistaxis) and 3% with the intact capsule (two subjects: two reported headache and one reported nausea). In the study involving lansoprazole 30 mg, the incidence of adverse events was 0% with the orally disintegrating tablet and 2% with the intact capsule (one subject experienced hyperlipidaemia). No clinically significant changes from baseline were observed for any other laboratory evaluation, vital sign parameter or physical examination finding in any subject.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References

These two studies are the first to compare the bio-equivalence of a novel orally disintegrating tablet formulation of lansoprazole with that of the same dose administered as an intact capsule. Comparison of the pharmacokinetic parameters Cmax, AUCt and AUC between the 15-mg lansoprazole orally disintegrating tablet and the 15-mg intact capsule and between the 30-mg lansoprazole orally disintegrating tablet and the 30-mg intact capsule indicated that the two dosage formulations are bio-equivalent, as the 90% confidence intervals for each of these measured parameters were entirely contained within the 0.80–1.25 range for bio-equivalence.

Statistically significant differences were observed only for period and sequence effects for λz in the lansoprazole 15 mg study, and the period effect for λz and the sequence effects for Tmax and Cmax in the lansoprazole 30 mg study. Five of the subjects enrolled exhibited lansoprazole half-lives of longer than 2 h. With the exception of one of these subjects, these individuals were administered lansoprazole 15 mg as the intact capsule first, followed by the orally disintegrating tablet. Therefore, the statistically significant sequence effect for λz observed in the lansoprazole 15 mg study may have been due to an unequal distribution of subjects with slightly longer t1/2 values between the sequence groups.

The Cmax and AUC values of a single dose of lansoprazole 30 mg administered as either the fast disintegrating tablet or the intact capsule in this study were consistent with the results observed in previous pharmacokinetic studies.1, 6, 23In previous studies, the values of Cmax and AUC after a single dose of lansoprazole 30 mg were similar to those observed following 5 days of administration, suggesting that the maximal pharmacokinetic and pharmacodynamic effects are achieved after the first dose.

The pharmacokinetic parameters obtained in this study are consistent with those recently observed in two studies by Huang et al.,23 and in earlier investigations by Tolman6 and Bell and Hunt.1

Lansoprazole administered orally has been observed to be extremely safe and well tolerated in large US and European studies,24, 25 a finding reiterated in this novel dosage formulation study. Based on the observations in this study, there is little or no evidence to suggest that the two dosage formulations of lansoprazole differ with regard to the incidence, severity or type of adverse events.

The once-daily administration of lansoprazole as an intact oral capsule, or as various preparations involving the capsule granules, is convenient; however, there are clinical and social situations in which the ability to administer an orally disintegrating proton pump inhibitor tablet without the need of liquid or soft food would be beneficial. The tablet contains enteric-coated microgranules of lansoprazole. Within approximately 30–60 s after being placed on the tongue, the tablet dissolves and the individual swallows the granules, without chewing and without swallowing additional liquid. The microgranules then pass through the acidic environment of the stomach and are dissolved and absorbed in the duodenum. Those who cannot tolerate the administration of oral liquids or soft foods (e.g. patients who are NPO (take nothing orally), critically ill patients in intensive or critical care units and those undergoing emergent or elective surgical procedures) would benefit from this type of orally administered agent. The use of an orally disintegrating tablet of lansoprazole in these individuals would eliminate the need for intravenous acid inhibitory therapy. In addition, ambulatory patients and individuals residing in long-term care facilities (and their care-givers) would find the ability to place an effective acid antisecretory agent on the tongue without the need for water extremely convenient for acute as well as long-term therapy of acid-related disorders.

In conclusion, these findings confirm that lansoprazole 15-mg and 30-mg orally disintegrating tablets are bio-equivalent to the respective 15-mg and 30-mg intact capsules, both administered orally. The ability to administer an effective and safe proton pump inhibitor, such as lansoprazole, to patients who have difficulty in swallowing, or who are unable or unwilling to swallow oral liquid/soft food formulations of the capsule granules, represents a highly desirable and novel therapy for the treatment of acid-related disorders.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Patients
  6. Study design
  7. Pharmacokinetic blood sample collection and analysis
  8. Pharmacokinetic and statistical analyses
  9. Results
  10. Discussion
  11. Acknowledgement
  12. References
  • 1
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    Blum RA, Shi H, Karol M, et al. The comparative effects of lansoprazole, omeprazole, and ranitidine in suppressing gastric acid secretion. Clin Ther 1997; 19: 101323.
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    Takeda H, Hokari K, Asaka M. Evaluation of the effect of lansoprazole in suppressing acid secretion using 24-hour intragastric pH monitoring. J Clin Gastroenterol 1995; 20(Suppl. 1): S79.
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    Bruley des Varannes S, Levy P, Lartigue S, et al. Comparison of lansoprazole with omeprazole on 24-hour intragastric pH, acid secretion, and serum gastrin in healthy volunteers. Aliment Pharmacol Ther 1994; 8(3): 30914.
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    Dammann HG, Fuchs W, Richter G, et al. Influence of lansoprazole 15 mg and omeprazole 20 mg and 40 mg on meal-stimulated gastric acid secretion. Aliment Pharmacol Ther 1997; 11: 35964.
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    Roberts KW, Pitcher WD, Cryer B. Effect of lansoprazole suspension versus continuous intravenous ranitidine on gastric pH of mechanically ventilated intensive care unit patients. Crit Care Med 2000; 28(Suppl. 12): A185(567/T155).
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    Metropolitan Life Insurance Company. Metropolitan height and weight tables. Stat Bull Metrop Life Found 1983; 64(1): 29.
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