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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background : Oral pancreatic enzyme supplements should be properly administered in order to ensure an adequate gastric mixing with the food and simultameous gastric emptying with the chyme.

Aim : To evaluate, in a prospective, randomized, open, comparative, three-way, crossover study, the effect of the administration schedule on the efficacy of oral pancreatic enzymes for the treatment of exocrine pancreatic insufficiency.

Methods : Twenty-four consecutive chronic pancreatitis patients with maldigestion secondary to exocrine pancreatic insufficiency were treated with 40 000 U lipase in the form of capsules containing enteric-coated mini-microspheres. Capsules were taken just before meals (schedule A), just after meals (schedule B) or distributed along with meals (schedule C) for three consecutive 1-week crossover periods in a randomized order. Fat digestion before and during the three treatment periods was evaluated by an optimized mixed 13C-triglyceride breath test.

Results : Before therapy, the 13CO2 recovery in the breath test was 23.8 ± 15.8% (normal >58.0%). During therapy, the 13CO2 recovery tended to be higher when capsules were taken along with meals (13CO2 recovery 61.4 ± 21.4%) or just after meals (13CO2 recovery 60.6 ± 21.8%) than when taken just before meals (13CO2 recovery 53.9 ± 20.3%). The percentage of patients who normalized fat digestion under therapy was 50, 54 and 63% with schedules A, B and C respectively.

Conclusions : The efficacy of pancreatic enzyme supplements for the treatment of exocrine pancreatic insufficiency may be optimized by administration during or after meals.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Maldigestion secondary to exocrine pancreatic insufficiency is a major complication of chronic pancreatitis. This occurs when postprandial secretion of pancreatic enzymes is reduced to levels below 10% of normal.1, 2 In addition, exocrine pancreatic insufficiency leading to maldigestion is a frequent finding in other diseases of the pancreas, such as cystic fibrosis, pancreatic cancer and following a severe attack of acute necrotizing pancreatitis.3–5 Patients with primary diabetes mellitus have also been found to be at risk for development of exocrine pancreatic insufficiency.6 Finally, patients who underwent partial or total surgical resection of the stomach, duodenum and/or pancreas suffer very frequently from primary and secondary exocrine pancreatic insufficiency associated with maldigestion.7

Oral supplements of pancreatic enzymes are widely accepted as the therapy of choice for maldigestion secondary to exocrine pancreatic insufficiency of any aetiology.8 Because of problems related to acid-mediated inactivation of lipase and because of the need for an adequate gastric mixture and emptying of enzymes with the nutrients, enteric-coated mini-microspheres are generally the preferred pharmacological formulation of pancreatic enzymes.9 Enteric-coated mini-microspheres have been shown to be emptied from the stomach together with the nutrients, to release the active pancreatic enzymes within the proximal intestine, with a high therapeutic efficacy.10–14

In addition to an optimal pharmacological formulation, oral supplements of pancreatic enzymes should be properly administered in order to ensure an adequate gastric mixing with the food and simultaneous gastric emptying with the chyme. Both gastric mixing and emptying with the nutrients are key steps for maximal lipolytic activity of the exogenous enzymes within the proximal intestine and thus for optimal therapeutic efficacy of the enzyme formulation. With this aim, a prandial administration of oral pancreatic enzymes is more convenient than an hourly administration over the day.15 However, no study has hitherto focused on the relevance of an adequate administration schedule in relation to meals on the efficacy of the enzyme substitution therapy for the treatment of maldigestion secondary to exocrine pancreatic insufficiency. From a theoretical point of view, if exogenous enzymes are taken before the meal, only part of the meal would most probably be properly digested, as enzymes will be totally emptied from the stomach before gastric emptying of the meal is completed. On the contrary, if exogenous enzymes are taken after the meal, a proportion of nutrients would be emptied from the stomach before enzymes have been ingested and digestion would therefore be inadequate. These two schedules are however the frequent means by which pancreatic enzyme supplements are administered.

We hypothesize that oral intake of exogenous pancreatic enzymes in different sub-doses distributed along with the meal may be more efficacious in improving digestion in patients with exocrine pancreatic insufficiency than taking the whole enzyme dose either before or after the meal. Therefore, the present study was primarily designed to assess the efficacy of a portioned administration of oral pancreatic enzymes along with meals in comparison with a single intake just before or after meals in the treatment of maldigestion secondary to exocrine pancreatic insufficiency. As a secondary aim, the subject's preference regarding the treatment administration schedule was evaluated.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

A prospective, randomized, open, comparative, crossover clinical trial of three different administration schedules of oral pancreatic enzymes in the form of enteric-coated mini-microspheres was carried out in patients with maldigestion because of exocrine pancreatic insufficiency secondary to chronic pancreatitis.

Patients

Consecutive out-patients referred to the Pancreas Section of the Department of Gastroenterology of the University Hospital of Santiago de Compostela, Spain, for suspected chronic pancreatitis were considered for the study. A final diagnosis of severe chronic pancreatitis and exocrine pancreatic insufficiency with steatorrhea was required as inclusion criteria.

The following were considered as exclusion criteria: patients who suffered from an acute relapse of pancreatitis within the 6 months preceding the study; subjects who were unable or unwilling to understand the study and sign the informed consent, or to return for the required study visits; any known gastrointestinal illness (e.g. celiac disease), hepatic disease (e.g. severe liver cirrhosis) or major gastrointestinal or pancreatic surgery that potentially affect the intestinal absorption or metabolism of fat; any severe restrictive pulmonary disease that is associated with a limited ability for CO2 elimination; gastroparesia of any aetiology; following general ethical rules, any known severe cardiovascular, renal, hepatic, pulmonary or mental disorder, malignancy or known human immunodeficiency virus (HIV) infection; and finally, pregnancy or lactation. Excessive alcohol intake, drug abuse or concomitant treatment with any medication influencing gastrointestinal physiology (e.g. H2-receptor blockers or proton-pump inhibitors) at the time of the study were also considered as exclusion criteria. It was foreseen that subjects, who withdraw their consent, do not follow properly the study protocol or do not perform all study visits and investigations should be withdrawn from the study.

Study protocol

Each potentially eligible patient had to complete a screening period, during which a medical history was taken, physical examination and standard haematological and biochemical laboratory tests carried out, the diagnosis of severe chronic pancreatitis and maldigestion secondary to exocrine pancreatic insufficiency established and the absence of exclusion criteria confirmed. Severe chronic pancreatitis was diagnosed by magnetic resonance imaging (MRI) pancreatography, computed tomography (CT) scan and/or endoscopic ultrasound according to the Cambridge and Wiersema criteria.16, 17 Diagnosis of steatorrhea was based on faecal fat quantification by near-infrared analysis in stool samples collected over the last 72 h of a 5-day period of standardized diet containing 92 g of fat per day.18

Included patients were treated with oral pancreatic enzyme supplements in the form of capsules containing enteric-coated mini-microspheres (Creon 10,000; Solvay Pharmaceuticals, Hannover, Germany) for three consecutive crossover 1-week periods. Four capsules were administered together with each of the three main daily meals (40 000 U lipase per meal). Three different administration schedules were evaluated:

  • Schedule A: four capsules just before meals (schedule 4–0–0)

  • Schedule B: four capsules just after meals (schedule 0–0–4)

  • Schedule C: one capsule just before meals, two during and one just after meals (schedule 1–2–1).

Schedules were administered according to a previously computer-generated random allocation order that defined six different sequences (Figure 1). The corresponding sequence was concealed until intervention was assigned. The allocation sequence was provided by a researcher (MIR) to the two investigators enrolling participants (JEDM, JIG). Participants and researchers administering the treatment were aware of the administration schedule and sequence. However, the investigators assessing the outcomes (AF, MVI) were blinded to group assignment.

image

Figure 1. Diagram of the study protocol and flow of participants. All patients were crossover-treated with oral pancreatic enzymes following the three administration schedules evaluated (4–0–0, 0–0–4 and 1–2–1) for three consecutive 1-week periods. Fat digestion was evaluated by means of the 13C-mixed triglyceride breath test (13C-MTG) the day before randomization (day 0) and at the last day of the three crossover periods (days 7, 14 and 21). Each one of the six lines represents a different schedule sequence.

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All medications (prescriptions or over-the-counter (OTC) medications) prescribed previously to the study or started during the study were documented. Medications that could affect the effect of oral pancreatic enzyme supplements, such as gastric acid secretion inhibitors, were avoided.

Fat digestion was evaluated by a previously optimized, standardized and validated breath test19 the day before randomization (basal) and at the last day of the three crossover periods (Figure 1). For breath test, 250 mg of mixed 13C-triglycerides (13C-MTG; Isomed S.L., Madrid, Spain) was orally given together with a standard solid test meal containing 16 g of fat (two toasts of white bread, 20 g butter and 200 mL water) after an overnight fast. The substrate was spread on the butter for an optimal mixture. As previously described, metoclopramide 10 mg was orally given 30 min before the breath test in order to avoid potential problems related to gastric emptying. Capsules of pancreatic enzymes were taken together with the test meal according to the corresponding administration schedule (A, B or C). Breath samples were collected in Exeteiner tubes (Labco Ltd, Brow Works, High Wycombe, UK) before the ingestion of the test meal and at 15-min intervals for 6 h. The quotient 13CO2/12CO2 was measured in each breath sample by mass spectrometry (BreathMat, Finnigan, Germany) and the global 6-h cumulative recovery rate of 13CO2 was considered as the result of the test. Based on previous studies, a 13CO2 recovery rate higher than 58% is considered to be normal.19

Sample size calculation

Sample size was calculated with the help of the software provided by Schoenfeld,20 by considering a two-sided α-error of 0.05, a statistical power of 0.8 and a minimal detectable difference between the most and the less effective administration schedule of 10% in the cumulative 13CO2 recovery rate. A within-patient standard deviation of 12% was considered based on the results obtained from the first 18 patients, in whom an interim analysis for variability calculation was conducted. Based on these figures, the total number of patients to be included in the crossover design to detect an efficacy difference between administration schedules was 24.

End-points and data analysis

As primary end-point, the therapeutic efficacy of oral pancreatic enzyme supplements for improving fat digestion according to the administration schedule was defined by the 6-h cumulative recovery rate of 13CO2 as measured by the 13C-MTG-breath test. Distribution of quantitative data was analysed by the Kolmogorov–Smirnov test. Descriptive data are expressed as mean ± s.d. The therapeutic efficacy of oral pancreatic enzyme supplements according to the administration schedule was tested by multivariate analysis with generalized linear mixed models (GLMM).21 These results are expressed as coefficient (difference in therapeutic efficacy between schedules) and 95% confidence interval (95% CI). The efficacy of the therapy was controlled by the potential confounding effect of both schedule and sequence order. Subject's preference regarding the treatment administration schedule was also assessed and analysed by the chi-square test. Data analysis was performed by the statistics software, S-Plus 6, in which the GLMM function is provided by the library MASS of Venables and Ripley.22

Ethical considerations

The study was conducted in accordance with the current guidelines of good clinical practice. The study protocol was approved by the Regional Committee for Ethics and Clinical Research. Patients participated voluntarily in the study after the investigator explained it properly. A written, dated and signed informed consent was obtained from all subjects before entry into the study.

All patients included in the study suffered from maldigestion secondary to exocrine pancreatic insufficiency and thus a therapy with oral pancreatic enzymes was required. Only the administration schedule of the therapy was tested. The 13C-MTG-breath test is being used routinely for the diagnosis of maldigestion at the Department of Gastroenterology of the University Hospital of Santiago de Compostela, Spain. The triglycerides used as substrate consist of a mixture of long- and medium-chain fatty acids that are usually present in the food. Furthermore, 13C is a stable isotope, nonradioactive, without any adverse effect as it is a part of the normal diet (carbohydrates).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

A total of 24 patients (19 male, five females, mean age 50 years, age range 36–76 years) were included. Severe chronic pancreatitis was diagnosed by MRI pancreatography and endoscopic ultrasound in all patients. Eight patients additionally underwent a CT scan that confirmed the diagnosis. All patients had steatorrhea, with a fat excretion of 18.8 ± 11.0 g/day. Four patients were assigned to each of the six schedule sequences; all of them completed the study protocol and were analysed for the primary outcome; none of them had to be withdrawn.

The 6-h cumulative recovery rate of 13CO2 before therapy was 23.8 ± 15.8% (normal >58%). Independent of the administration schedule, therapy with oral pancreatic enzymes (40 000 U lipase in enteric-coated mini-microspheres per meal) improved fat digestion and increased the 6-h cumulative recovery rate of 13CO2 by 34.8% (95% CI 27.3–42.4; P < 0.001 compared with basal value) (Figure 2). Up to 63% of patients normalized fat digestion (normal 13C-MTG breath test result) with the given dose of 40 000 U lipase per meal.

image

Figure 2. Results (mean and SD) of the 13C-mixed triglyceride breath test before and during exogenous enzyme therapy with the three different administration schedules. Fat digestion, as expressed by the 13CO2 recovery rate, improved significantly during enzyme therapy independent of the administration schedule used (P < 0.0001, any treatment compared with basal value). Fat digestion tends to be better with treatment schedules B and C than with schedule A (P = 0.18 and 0.14, respectively compared with A). The lower limit of normal of the test is shown as a dotted line.

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Efficacy of oral pancreatic enzymes for improving fat digestion tended to be higher when capsules were taken along with the meal (schedule C, 13C-MTG breath test result 61.4 ± 21.4%) or just after the meal (schedule B, 13C-MTG breath test result 60.6 ± 21.8%) than when they were taken just before the meal (schedule A, 13C-MTG breath test result 53.9 ± 20.3%) (Figure 2). After adjusting by schedule and sequence order, schedules B and C allowed to improve fat digestion (6-h cumulative recovery rate of 13CO2) by 6.7% (95% CI −3.0 to 16.4) and 7.5% (95% CI −2.2 to 17.2), respectively, in relation to schedule A (P = 0.185 and 0.138, respectively). The percentage of patients who normalized fat digestion (normal 13C-MTG breath test result) was 50, 54 and 63% with schedules A, B and C respectively (N.S.). No confounding effect by the schedule order could be detected by GLMM analysis (Table 1). However, there was some confounding effect of the sequence order after adjusting for schedule order (Table 2). Results of fat digestion during therapy with oral pancreatic enzymes according to the order in which each one of the administration schedules was given is shown in Figure 3.

Table 1.  Analysis of the confounding effect of the administration schedule order (see Figure 1 for details) on the efficacy of oral pancreatic enzymes for the treatment of fat maldigestion
 Coefficient95% CIP-value
Intercept54.143.9 to 70.2<0.001
Schedule B6.7−2.8 to 16.20.175
Schedule C7.5−2.0 to 17.00.129
Schedule order 2−1.1−10.6 to 8.390.813
Schedule order 30.7−8.8 to 10.20.885
Table 2.  Analysis of the confounding effect of the sequence order of administration schedules (see Figure 1 for details) on the efficacy of oral pancreatic enzymes for the treatment of fat maldigestion
 Coefficient95% CIP-value
Intercept59.945.7 to 74.0<0.001
Schedule B6.7−3.0 to 16.40.185
Schedule C7.5−2.2 to 17.20.138
Sequence 2−11.6−29.9 to 6.70.229
Sequence 3−1.9−20.2 to 16.40.841
Sequence 4−3.3−21.6 to 15.00.725
Sequence 56.1−12.2 to 24.40.526
Sequence 6−24.9−43.2 to −6.60.016
image

Figure 3. Results (mean and s.d.) of the 13C-mixed triglyceride breath test during exogenous enzyme therapy with the three different administration schedules (A, B and C) according to the randomization order (1st, 2nd or 3rd) in which each one of these schedules was given.

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Pancreatic enzyme substitution therapy at the dose used in this study was well tolerated and no adverse event was reported by any patient. Regarding patient preference, no administration schedule was found to be significantly more frequently preferred than the others (Figure 4). Administration of the medication along with the meal (schedule C) tended to be more frequently preferred (25.0% of patients) than all capsules together just after the meal (schedule B, 16.7% of patients). Almost one-third of the patients showed no preference between the three administration schedules.

image

Figure 4. Patient preference regarding the oral pancreatic enzymes administration schedules. The percentage of patients preferring any of the administration schedules tested is shown. No significant difference was obtained between schedules.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Maldigestion secondary to exocrine pancreatic insufficiency is, together with pain, the major clinical manifestation of chronic pancreatitis. From a clinical and therapeutic point of view, fat maldigestion, which develops once pancreatic lipase secretion is below 10% of normal, is more relevant than protein and carbohydrate maldigestion.1, 2 The first step in the management of chronic pancreatitis is the avoidance of alcohol intake. Alcoholic abstinence does not only provide pain relief in around half of patients, but it also induces an increase of gastric lipase secretion thus improving fat digestion.23

Oral pancreatic enzyme supplements are the treatment of choice of maldigestion secondary to exocrine pancreatic insufficiency.8, 9, 24 Enteric-coated mini-microspheres have been developed in order to facilitate an optimal intragastric mixture of the exogenous enzymes with the meal and a simultaneous gastric emptying of the enzymes with the chyme.10–14 With the same objective, the timing of oral enzyme administration with meals should be optimized. Nearly 30 years ago, DiMagno et al.15 showed that prandial administration of oral enzymes was as effective as hourly administration over the day in decreasing steatorrhea. In that small study involving six patients and six healthy controls, they recommended for the first time, a prandial administration of oral enzymes, because that schedule was more convenient. The present study is a further step in this context, as different prandial administration schedules are evaluated. In fact, it is widely accepted that pancreatic enzymes should be given at meals, but information regarding the effect of different prandial administration schedules (just before, during or just after meals) on the efficacy of the enzyme substitution therapy is lacking. This aspect is answered in the present study. In addition, pancreatic enzymes in DiMagno's study were given in tablet form, whereas the present study evaluates the most modern pharmacological formulation in enteric-coated mini-microspheres.

The present study demonstrates that oral pancreatic enzymes in the form of enteric-coated mini-microspheres are highly effective in improving fat maldigestion secondary to exocrine pancreatic insufficiency independent of the administration schedule. However, the proportion of fat digested tends to be higher when exogenous enzymes are given either just after meals or, even better, distributed along with meals than when given just before meals. Compared with the intake of the enzymes just before the meal, fat digestion improves by 6.6% and 7.5% when they are taken just after or along with the meal respectively. These differences, although statistically not significant, may be considered as clinically relevant.

It appears logical that the intragastric mixture of exogenous enzymes with nutrients should be more adequate when enzymes are taken along with the meal than before or after the meal. This is supported by the fact that up to 13% more patients are able to normalize fat digestion when the same amount of enzymes is orally given along with the meal than just after or just before the meal. It should however be noted that oral pancreatic enzymes are also highly effective in treating fat maldigestion when administered just before or after meals. Thus, although exogenous enzymes that are taken before meals may be emptied from the stomach before gastric emptying of the meal is completed, a relevant part of the nutrients are properly digested. Similarly, a relevant proportion of the meal is properly digested when exogenous enzymes are taken just postprandially, despite part of nutrients could be emptied from the stomach before enzymes have been ingested.

In the present study, both patients and researchers administering the interventions were aware of the treatment schedules; however, the researchers assessing the outcomes were blinded to group assignment. In addition, the random allocation sequence, the crossover study design, the multivariate analysis controlling for the potential confounding effect of the schedule order and sequence, and the use of objective data (fat absorption) as main variable assure the relevance of the results here reported.

It could be also argued that enzyme administration distributed along with the meal could be more difficult to be accomplished and that patients could prefer the intake of enzymes as a single dose just before or after the meal. This could not be confirmed in the present study, in which the three schedules evaluated were similarly preferred.

The last relevant point for discussion refers to the method applied for evaluation of fat digestion. The 13C-mixed triglyceride breath test as pancreatic function test was reported some years ago by Vantrappen et al.25 The 13C-MTG breath test protocol used in the present study for evaluation of fat digestion was previously optimized and validated by our research group after testing different substrates, substrate doses and test meals.19 The sensitivity and specificity of the described 13C-MTG breath test for the diagnosis of fat maldigestion in patients with chronic pancreatitis are both >90% compared with faecal fat quantification by near-infrared analysis. Thus, the optimized 13C-MTG breath test is a simple and accurate alternative to faecal fat quantification for the evaluation of fat digestion. In addition, we previously demonstrated that this breath test is highly accurate for the evaluation of the efficacy of oral pancreatic enzymes as therapy of exocrine pancreatic insufficiency.26

In conclusion, exogenous pancreatic enzymes (40 000 U lipase per meal) in enteric-coated mini-microspheres are highly effective for the treatment of exocrine pancreatic insufficiency secondary to chronic pancreatitis independent of the administration schedule used. In order to obtain an optimal therapeutic effect, it may be recommended to administrate oral enzymes just after meals or, even better, distributed along with meals. Patient preference and tolerance to exogenous enzymes are not affected by the administration schedule.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study has been partially supported by the Health Institute Carlos III, Grant ref. GO3/156, Ministry of Health, Spain, together with a research grant of Solvay Pharmaceuticals, Germany.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    DiMagno EP, Go VLW, Summerskill HJ. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. New Engl J Med 1973; 288: 8135.
  • 2
    Lankisch PG, Lembcke B, Wengen G, Creutzfeldt W. Functional reserve capacity of the exocrine pancreas. Digestion 1986; 35: 17581.
  • 3
    Modolell I, Alvarez A, Guarner L, De Gracia J, Malagelada JR. Gastrointestinal, liver, and pancreatic involvement in adult patients with cystic fibrosis. Pancreas 2001; 22: 3959.
  • 4
    Perez MM, Newcomer AD, Moertel CG, Go VLW, DiMagno EP. Assessment of weight loss, food intake, fat metabolism, malabsorption, and treatment of pancreatic insufficiency in pancreatic cancer. Cancer 1983; 52: 34652.
  • 5
    Tsiotos GG, Luque-de Leon E, Sarr MG. Long-term outcome of necrotizing pancreatitis treated by necrosectomy. Br J Surg 1998; 85: 16503.
  • 6
    Hardt PD, Hauenschild A, Jaeger C, Teichmann J, Bretzel RG, Kloer HU. High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations: a prospective multicenter study. Dig Dis Sci 2003; 48: 168892.
  • 7
    Friess H, Böhm J, Müller MW, et al. Maldigestion after total gastrectomy is associated with pancreatic insufficiency. Am J Gastroenterol 1996; 91: 3417.
  • 8
    Layer P, Keller J. Lipase supplementation therapy: standards, alternatives, and perspectives. Pancreas 2003; 26: 17.
  • 9
    Dutta SK, Rubin J, Harvey J. Comparative evaluation of the therapeutic efficacy of a pH-sensitive enteric coated pancreatic enzyme preparation with conventional pancreatic enzyme therapy in the treatment of exocrine pancreatic insufficiency. Gastroenterology 1983; 84: 47682.
  • 10
    Halm U, Loser C, Lohr M, Katschinski M, Mossner J. A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency. Aliment Pharmacol Ther 1999; 13: 9517.
  • 11
    Layer P, Holtmann G. Pancreatic enzymes in chronic pancreatitis. Int J Pancreatol 1994; 15: 111.
  • 12
    Kühnelt P, Mundlos S, Adler G. The size of enteric coated microspheres influences the intraduodenal lipolytic activity. Z Gastroenterol 1991; 29: 41721.
  • 13
    Meyer JH, Elashoff J, Porter-Fink V, Dressman J, Amidon GL. Human postprandial gastric emptying of 1–3 millimeter spheres. Gastroenterology 1988; 94: 131525.
  • 14
    Domínguez-Muñoz JE, Birkelbach U, Glasbrenner B, Sauerbruch T, Malfertheiner P. Effect of oral pancreatic enzyme administration on digestive function in healthy subjects: comparison between two enzyme preparations. Aliment Pharmacol Ther 1997; 11: 4038.
  • 15
    DiMagno EP, Malagelada JR, Go VL, Moertel CG. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med 1977; 296: 131822.
  • 16
    Axon ATR, Classen M, Cotton PB, Cremer M, Freeny PC, Lees WR. Pancreatography in chronic pancreatitis: international definitions. Gut 1984; 25: 110712.
  • 17
    Wiersema MJ, Hawes RH, Lehman GA, Kochman ML, Sherman S, Kopecky KK. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangio pancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 1993; 25: 55564.
  • 18
    Stein J, Purschian B, Bieniek U, Caspary WF, Lemcke B. Near-infrared reflectance analysis (NIRA): A new dimension in the investigation of malabsorption syndromes. Eur J Gastroenterol Hepatol 1994; 6: 88994.
  • 19
    Iglesias-García J, Vilariño M, Iglesias-Rey M, Lourido MV*, Domínguez-Muñoz JE. Accuracy of the Optimized 13C-mixed triglyceride breath test for the diagnosis of steatorrhea in clinical practice. Gastroenterology 2003; 124 (suppl 1): A-631.
  • 20
    Schoenfeld DA. Find Statistical Considerations for a Cross-over Study where the Outcome is a Measurement, 1995. Available at: http://hedwig.mgh.harvard.edu/sample_size/quan_measur/cross_quant.html. Accessed 6 November 2002.
  • 21
    Breslow NE, Clayton DG. Approximate inference in Generalized Linear Mixed Models. J Am Stat Assoc 1993; 88: 925.
  • 22
    Venables WN, Ripley BD. Modern Applied Statistics with S-PLUS. Oxford: Springer, 1999.
  • 23
    Gullo L, Barbara L, Labò G. Effect of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology 1988; 95: 10638.
  • 24
    Vuoristo M, Vaananen H, Miettinen TA. Cholesterol malabsorption in pancreatic insufficiency: Effects of enzyme substitution. Gastroenterology 1992; 102: 64755.
  • 25
    Vantrappen GR, Rutgeerts PJ, Ghoos YF, Hiele MI. Mixed triglyceride breath test: a noninvasive test of pancreatic lipase activity in the duodenum. Gastroenterology 1989; 96: 112634.
  • 26
    Iglesias-García J, Iglesias-Rey M, Vilariño-Insua M, Domínguez-Muñoz JE. Evaluation of the efficacy of oral pancreatic enzyme substitution therapy in patients with exocrine pancreatic insufficiency: Evaluation with optimized 13C-mixed triglyceride breath test. Gastroenterology 2004; 126 (suppl 1): A-29.