Pharmacy and Therapeutics Committee Meeting of September 13, 2005 Kellogg Center, Michigan State University MEETING MINUTES I. Welcome and Introductions, and Approval of June 7, 2005 Meeting Minutes The meeting was called to order at 6:00PM by Richard Slaughter, Chair. In attendance were Richard Slaughter, MSc., D.VanLoo, PharmD., M. Robins DO, G. Perri, MD, Jonathan Arend, Ph
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Oral xylose isomerase decreases breath hydrogen excretion and improves gastrointestinal symptoms in fructose malabsorption a doubleblind, placebocontrolled studyOral xylose isomerase decreases breath hydrogen excretionand improves gastrointestinal symptoms in fructosemalabsorption – a double-blind, placebo-controlled study P. Komericki*, M. Akkilic-Materna*, T. Strimitzer†, K. Weyermair†, H. F. Hammer‡ & W. Aberer* Dermatology and Venereology,Medical University of Graz, Graz, Austria.
†Austrian Agency for Health and Food Incomplete resorption of fructose results in increased colonic hydrogen pro- duction and is a frequent cause of abdominal symptoms. The only treat- ‡Division of Gastroenterology andHepatology, Department of InternalMedicine, Medical University of Graz, To study whether orally administered xylose isomerase (XI), an enzymethat catalyses the reversible isomerisation of glucose and fructose, candecrease breath hydrogen excretion in patients with fructose malabsorption.
Correspondence to:Prof. Dr P. Komericki, Department of Environmental Dermatology andVenereology, Medical University of Patients received 25 g fructose in 100 mL water together with either pla- cebo or XI capsules. Primary endpoint was the reduction in breath hydro- gen excretion, as assessed by the area under the breath hydrogen curve over 4 h (AUC). A secondary endpoint was the reduction in abdominalpain, bloating and nausea assessed on a visual analogue scale (VAS, range: 0–10). A P value <0.05 was considered statistically signiﬁcant.
Sixty-ﬁve patients in whom fructose malabsorption had been diagnosed by positive breath hydrogen test within the previous year, were included in thestudy [15 males, 50 females; mean age 43.3 (s.d. = 14.4), range:21–73 years]. The median AUC was 885 ppm/240 min in the XI groupcompared to 2071 ppm/240 min in the placebo group (P = 0.00). Medianscores for abdominal pain (0.7 vs. 1.3) and nausea (0.2 vs. 0.6), but not forbloating (P = 0.053), were signiﬁcantly improved after XI (P = 0.009 andP = 0.005) as compared with placebo.
ConclusionsOral administration of xylose isomerase signiﬁcantly decreased breathhydrogen excretion after ingestion of a watery fructose solution. Nauseaand abdominal pain were signiﬁcantly improved by xylose isomerase.
breath hydrogen test. The sensitivity of this breath Fructose is present in modern diets either as a constitu- hydrogen test, however, is inﬂuenced by the prevalence ent of the disaccharide sucrose or as the monosaccha- of hydrogen non-excretion, which has been reported to ride. Average daily intake varies from 11 to 54 g.1 be up to 18%.24 Incomplete fructose absorption usually Fructose is used as a sweetener or as high fructose corn is identiﬁed by a positive result on a breath hydrogen syrup in soda, fruit juices or candy, and it is naturally test after ingestion of 25–50 g of fructose.
present in fruits like apples, peaches, pears and oranges.2 There is a lack of information on the prevalence of From 1970 to 1997, daily per capita intake of fructose incomplete absorption of fructose in the healthy popula- increased from below 1 g to over 70 g while consump- tion, but self selection of persons coming to the test may tion of sucrose, a disaccharide in which fructose is linked play an important role. In studies on small numbers of healthy subjects between 11% and 50% had a positive The absorptive capacity for fructose that is not accom- breath hydrogen test after 25 g of fructose, and between panied by glucose is small.4 The normal absorptive 38% and 81% of subjects had a positive breath hydrogen capacity for fructose depends on other nutrients as well, test after 50 g of fructose. In normal subjects who and still is poorly understood. It has been suggested that ingested 25 g of fructose, incomplete absorption docu- healthy subjects have the capacity to absorb up to 25 g mented by a positive hydrogen breath test had only a of fructose, whereas many have incomplete absorption marginal effect on symptoms, whereas after 50 g of fruc- and intolerance with intake of 50 g of fructose.5 Inges- tose there was a more pronounced effect on symptoms tion of food that contains fructose in excess of glucose in previously asymptomatic normal subjects with docu- may result in symptoms such as abdominal bloating or diarrhoea and also may provoke symptoms in patients The same review also summarised results of hydrogen with irritable bowel syndrome (IBS).6–8 It has been sug- breath testing in patients with functional gut disorders.1 gested that as little as 3 g of fructose may induce symp- In these patients, the prevalence of a positive hydrogen toms in functional bowel disorders. Gender may breath test after 25 g of fructose was between 39% and 80%, increasing with the concentration of the fructose Incompletely absorbed fructose reaches the colon, where bacterial carbohydrate metabolism results in pro- When studies in patients or normal subjects using duction of short chain fatty acids and gases like hydro- 25 g of fructose were compared, patients with functional gen. This may cause symptoms like abdominal pain, gut disorders and a positive hydrogen breath test in gen- bloating, discomfort and diarrhoea.10–12 These symptoms eral had a higher likelihood of symptoms as compared are not speciﬁc for fructose malabsorption but also occur with previously asymptomatic normal subjects with a with other incompletely absorbed carbohydrates, like die- positive breath hydrogen test. However, after 50 g of tary ﬁbres, sorbitol, lactose in case of lactase deﬁciency fructose, the proportion of patients with a positive or carbohydrate malabsorption in severe restriction of breath hydrogen tests and the proportion of patients pancreatic digestive or intestinal absorptive capac- who had symptoms related to incomplete fructose ity.11, 13–15 Recently the term FODMAP, describing fer- absorption was similar to normal subjects.1 These obser- mentable oligo-, di- and monosaccharides and polyols vations suggest that patients with functional gastrointes- has been used to characterise short chain carbohydrates tinal disorders may have a greater likelihood to be which potentially may trigger abdominal symptoms and referred to a fructose hydrogen breath test, and that they for which dietary restriction has been suggested to be may be more sensitive to lower doses of malabsorbed efﬁcacious.16, 17 Continued ingestion of high amounts of fructose has been suggested to result in a variety of other Xylose isomerase (XI, EC 22.214.171.124, CAS 9023-82-9) is impairments. Since the year 1975 it has been discussed an enzyme that catalyses the reversible isomerisation of that enhanced dietary fructose could induce obesity, glucose and fructose.26 It has been used for the industrial accelerated ageing, insulin resistance and non-alcoholic conversion of glucose to fructose in the manufacture of fatty liver disease.18–22 In addition, some types of depres- high fructose corn syrup.27 XI is available from industrial sion could be related to long time consumption of high production and has been proven not to provoke allergic reactions in man. Furthermore, GRAS (Generally Recog- Hydrogen produced in the colon is absorbed and nized As Safe) status of the enzyme has been afﬁrmed excreted in breath. This can be used for a diagnostic Xylose isomerase in fructose malabsorption We hypothesised that orally administered XI is able to under the breath hydrogen curve (AUC) over a 4 h catalyse the conversion of poorly absorbable fructose into observation period. AUC after fructose plus XI was com- well-absorbable glucose in the human intestine in vivo and pared with AUC after fructose plus placebo. Secondary thereby reduce breath hydrogen excretion after ingestion endpoint was the reduction of the symptoms abdominal of fructose in patients with incomplete fructose absorp- pain, bloating and nausea using a visual analogue score.
tion. To assess this hypothesis, we performed a double-blind randomised crossover study in patients with previously established fructose malabsorption. Breath The XI capsule (258.2 mg) (Fructosin; Sciotec, Tulln, hydrogen excretion was assessed in patients who received Austria) contains 43.12 mg of this enzyme showing an either XI or placebo with an oral watery fructose load. A activity of approximately 1.6 lkat per caps. Further secondary endpoint was the assessment of the effect of XI ingredients, amongst others are microcrystalline cellulose on symptoms using a visual analogue scale (VAS).
(70.43 mg), gelatine (47.24 mg), maltose (25.13 mg),shellac (20.4 mg). Placebo capsules are composed of microcrys-talline cellulose (200 mg) and gelatine (47.24 mg). To ensure reproducible activity of the enzyme a crystallisa- This randomised, double-blind, placebo-controlled, pro- tion process that yields highly active and stable crystals spective, crossover interventional study was conducted in of XI was developed (patent application EP2161034).
the Department of Environmental Dermatology and Ve- These crystals were then incorporated into small micro- nereology of the Medical University of Graz, Austria, pellets with a diameter of approximately 1 mm. This size from June 2009 until May 2010 in accordance with the ensures that pellets are emptied during the digestive principles of Good Clinical Practice (GCP) correspond- phase of stomach emptying.28 Pellets had an enteric ing to the ICH guidelines (International Conference on coating with a thin ﬁlm of shellac to protect the enzyme Harmonisation of drugs and medical devices).
from acidic denaturation during stomach transit. The The protocol was registered at ClinicalTrials.gov pellets were packed into gelatine capsules which dissolve (NCT00916487) and at EudraCT (EUDRACT2008- quickly in the stomach releasing the pellets.29 005861-80) and approved by the Ethics Committee ofthe Medical University of Graz (EK 20-024 ex 08/09).
Preparation, randomisation protocol and use of testkits The producer of XI capsules prepared numbered test kits The study was performed in patients who were referred containing (i) fructose for two tests (25 g each in two for a fructose hydrogen breath test for the evaluation of 100 mL plastic bottles), and (ii) three capsules of XI and abdominal symptoms, and in whom fructose malabsorp- three capsules of placebo which were randomly assigned tion was conﬁrmed within the preceding 12 months. Tests to sealed bags marked with ‘X’ and ‘Y’ respectively. Test were performed in the departments of gastroenterology or kits were sent by courier to the test centre. XI and pla- dermatology of our university. Fructose malabsorption cebo capsules looked and tasted identical. This procedure was conﬁrmed if there was an increase in end expiratory guaranteed blinding of researchers and participants. Sub- breath hydrogen concentration of at least 20 ppm over jects were randomised to groups A and B according to a baseline after 25 or 30 g of fructose; 30 g was used at the scheme deﬁned before starting inclusion and randomly department of gastroenterology and 25 g was used at the assigned to a predeﬁned test kit number. Subjects of department of dermatology. Exclusion criteria were preg- group A had to start with capsules contained in the nancy, breast feeding, diabetes mellitus and gastrointesti- sealed bag ‘X’, and subjects of group B started with cap- nal surgery, endoscopy or antibiotic treatment within the sules contained in bag ‘Y’. For the second test, the cap- preceding 4 weeks. Before enrolment, every patient signed sules in the remaining bag (Y or X, respectively) had to a declaration of consent after having been provided with be taken. Deblinding of test kits was done in a joint thorough verbal and written information.
meeting of investigators (P. K, T. S.) and representativesof the producer of capsules.
Therefore, randomisation was performed on several Primary endpoint was the assessment of breath H2 levels. XI and placebo capsules were randomly assigned to excretion after fructose intake by calculating the area sealed bags marked with ‘X’ or ‘Y’ for each test kit before test kit preparation. Test kits were numbered consecu- tively. Subjects were randomly assigned to a numbered Nonparametric methods were used for the inference sta- test kit and, independently, to group A and B. Assignment to groups A and B determined the order of use of bags ‘X’ The regular distribution analysis was performed and ‘Y’ for the ﬁrst or second test respectively. All ran- according to Kolmogorov-Smirnov and to Shapiro-Wilk.
domisation steps were performed according to lists pro- The Wilcoxon signed-rank test was used to compare the vided by a statistical institute (Data collection, Statistics, two related samples XI and placebo. A P value <0.05 Risk assessment; Austrian Agency for Health and Food was considered statistically signiﬁcant.
Safety) before starting package preparation and oral prov- The same statistical tests (Kolmogorov-Smirnov and ocations using the random sample SAS (9.2; SAS Inc., Wilcoxon) were used for the VAS symptom scores for bloating, abdominal pain and nausea.
Data were analysed with SAS 9.2 and SPSS version 19 Two tests were performed at an interval between 4 daysand 21 days. One day prior to each visit, subjects were asked to consume a lactose- and fructose-restricted diet.
Sixty-ﬁve patients (15 men and 50 women; mean age 43.3 All the subjects fasted overnight and were not allowed to (s.d. = 14.4), range: 21–73 years) participated in the smoke 12 h before the test. The fasting end expiratory study. No subject dropped out from the trial. One of 65 breath H2 concentration (termed 0 min) was measured tested subjects did not complete the symptom question- using a Gastro+ Gastrolyser (Bedfont Scientiﬁc Ltd, naire. In the current study, peak increases in end expira- Rochester, England) which has a sealed electrochemical tory hydrogen concentrations after fructose did not sensor speciﬁc for H2. Immediately thereafter subjects had exceed 20 ppm in 19 patients after placebo; after inges- to take three capsules ‘X’ or ‘Y’ and then to ingest 25 g of tion of XI, four of these patients had an increase in breath fructose freshly dissolved in 100 mL of mineral water hydrogen concentration after fructose exceeding 20 ppm.
taken from one single production batch which was added On the other hand, XI decreased peak hydrogen excretion to the plastic bottles which contained the fructose. Sub- after fructose to less than 20 ppm in 16 patients who had jects were advised to drink the solution within 5 min.
an increase exceeding 20 ppm after placebo.
Thereafter, end expiratory breath H2 concentration was The median AUC after 25 g of fructose was 885 ppm/ recorded every 30 min for the ﬁrst 2 h, then every 60 min 240 min (25th percentile 60, 75th percentile 4009) in the for the next 2 h (for a total of 240 min) by a study physi- XI group, and 2071 ppm/240 min (25th percentile 487, cian (M. A.-M.). The second test was performed identi- 75th percentile 5898) in the placebo group (Table 1, Fig- cally with the remaining capsules (‘Y’ or ‘X’).
ure 1). This difference in AUC was statistically signiﬁ-cant (Z-value À3.585, two-sided asymptotic signiﬁcance; P = 0.00) in favour to the XI group.
After plotting the breath H2 concentrations (in ppm) vs.
There were marked inter-individual differences in time for the 4 h observation period the area under the scores for all three symptoms, covering the whole range curve (AUC) was calculated for each subject for both of the VAS scale from 0 to 10. In general, bloating was tests and expressed as ppm/240 min. Fasting breath H2 scored to be the most bothersome symptom although its concentration at 0 min was used as the baseline for median score was only 0.8 (range: 0–8.2) in the placebo AUC determination. For example, if basal breath hydro- group and 0.2 (range: 0–10) in the XI group. This differ- gen concentration was 5 ppm, the AUC was calculated ence failed to reach statistical signiﬁcance (Z = À1.935, from the area under the curve exceeding this baseline of P = 0.053). Median scores for abdominal pain and nau- sea were signiﬁcantly lower after XI as compared withplacebo P = 0.005 respectively) (Table 2, Figure 2).
The symptoms bloating, nausea and abdominal painwere assessed individually before ingestion of the test solutions and at each time of breath hydrogen measure- Xylose isomerase (EC 126.96.36.199, CAS 9023-82-9), also ment by visual analogue scale covering a range of 0 referred to as glucose isomerase, is an enzyme that cataly- ses the chemical reaction D-xylose ⇌ D-xylulose and Xylose isomerase in fructose malabsorption AUC, area under curve; n, number; s.d., standard deviation; Min, minimum; Max, maxi-mum.
sule design has been used in the past for protecting drugs from the acidic environment of the stomach,allowing gastric emptying of micropellets with a size between 2 mm and 3 mm through the pylorus with food and quick release of the enzymes in the neutral environ- ment of the duodenum.29 Ingested watery solutions ofpoorly absorbable carbohydrates start reaching the cecum after an oro-cecal transit time of 60 ± 7 min [mean + standard deviation (s.d.)] in symptomatic and 96 ± 16 min (mean + s.d.) in asymptomatic persons32; during this time the enzyme presumably would catalyse the isomerisation of fructose to glucose, which is actively absorbed by the intestinal mucosa via the SGLT-1 trans-porter.33 We hypothesised that due to active absorption Figure 1 | Signiﬁcant reduction (P = 0.00) in the breath of glucose, the equilibrium of the isomerisation process hydrogen area under curve (AUC; ppm/240 min) in would be pushed towards glucose. As a consequence, less the XI group (n = 65) compared with the placebo fructose would enter the colon and be metabolised by group (n = 65) (logarithmic scaling). The median colonic bacteria, resulting in less hydrogen production, values for XI and placebo group were 885 and and possibly also reduced symptoms related to incom- To prove this hypothesis, we studied the effect of XI fructose ⇌ glucose.7 It has been used since 1957 industri- on breath hydrogen excretion after ingestion of fructose.
ally to convert glucose to fructose in the manufacture of Our study group consisted of patients who had presented high fructose corn syrup and is one of the highest tonnage for the evaluation of abdominal symptoms and in whom industrial enzymes.30, 31 Glucose isomerase enzyme prepa- fructose malabsorption was established within the previ- rations are used in the production of high fructose corn ous 12 months by the use of a fructose hydrogen breath syrup described in § 184.1866 of the FDA GRAS Notice test. It has been demonstrated in the past, that this Inventory. They are derived from recognised species of group may include patients with functional gastrointesti- precisely classiﬁed nonpathogenic and nontoxicogenic nal disorders who are more likely to develop symptoms microorganisms, including Streptomyces rubiginosus, Acti- at lower doses of ingested fructose,1 possibly representing noplanes missouriensis, Streptomyces olivaceus, Streptomy- visceral hypersensitivity which has been demonstrated in ces olivochromogenes and Bacillus coagulans, that have been grown in a pure culture fermentation that produces Although we had originally planned to repeat the fructose hydrogen breath test immediately before start of As XI is also able to convert poorly absorbable fruc- the study, this repeat procedure was declined by the tose to well-absorbable glucose in vitro, we hypothesised ethics committee of our university, to spare patients of that this enzyme could be used for conversion of excess the symptoms associated with an oral fructose load.
fructose to glucose in the human small intestine in vivo.
Unexpectedly, it turned out that in the course of the To test this hypothesis, capsules containing enteric study in 29% of patients the increase in end expiratory coated micropellets of XI were manufactured. This cap- hydrogen concentration was less than 20 ppm. This Table 2 | Symptom scores forabdominal pain, bloating and n, number; s.d., standard deviation; Min, minimum; Max, maximum; XI, xylose isomer-ase.
excess hydrogen production due to fructose malabsorp- tion. The dose of 25 g fructose in our study is on thelower end of the dose range which has been used by different authors.1 At this dose, patients with functionalgastrointestinal disorders are more likely to develop symptoms than normal subjects. This is relevant for thepotential clinical application of our study results, because if a drug treatment would be considered in fructose malabsorption, this should be limited to patients who develop symptoms, regardless whether ornot symptoms may be aggravated by an underlying vis- ceral hypersensitivity. Since pharmacological treatment options for functional gastrointestinal disorders are very limited detection of small amounts of fructose beingmalabsorbed has a clinical relevance, directing attention Figure 2 | XI signiﬁcantly reduced symptom scores for at excluding even small amounts of fructose from the abdominal pain (P = 0.009) and nausea (P = 0.005), but not for bloating (P = 0.053), in 64 patients who In this study, oral supplementation of XI revealed a received XI or placebo on two study days.
statistically signiﬁcant decrease in breath hydrogenexcretion over a 4 h period after ingestion of fructose,as compared with placebo. Decrease in the area under suggests a considerable intraindividual variability of the breath hydrogen curve after XI suggests that XI breath hydrogen excretion, which needs future attention catalysed the isomerisation of fructose which resulted in in trials using breath hydrogen test. In this context, it a lower amount of fructose reaching the colon. It is has to be kept in mind, that the cut off value of 20 ppm reasonable to end the measurement period at 4 h since which is commonly used clinically to establish malab- breath hydrogen excretion after ingestion of poorly sorption is only one point on the hydrogen excretion absorbable carbohydrates reaches its peak before that curve, plotted as hydrogen excretion over time. Consid- time. In a previous study on lactose malabsorption, erably more information on colonic gas production and hydrogen peak occurred at 160 ± 16 min (mean + s.d.), excretion can be gained from cumulative ﬂatus collec- regardless whether patients were symptomatic or not, tions or AUC.11, 36 In the current study, AUC was used and in a study with cumulative measurement of anal to assess colonic hydrogen accumulation over the curves ﬂattened after 210–240 min in the majority of In those patients who did not exceed the cut off level of 20 ppm, there was still a demonstrable increase A surprising ﬁnding in our study was, that, although in the breath hydrogen over the baseline, indicating patients had presented in the preceding year for evaluation Xylose isomerase in fructose malabsorption of abdominal symptoms, indicating that they were both- Future studies will have to demonstrate whether XI is ered by their symptoms enough to warrant diagnostic effective with carbohydrate mixtures which are present in evaluation at a tertiary care centre, only few patients had fructose containing food, and to assess long-term effects high scores on the VAS assessment of symptom severity and safety and to identify patients who most beneﬁt from during this study. This may indicate a large intra- the treatment. The presence of fructose malabsorption in individual variability in the severity of symptom scores patients with functional gut symptoms may represent not presumably associated with incomplete fructose absorp- only an opportunity for dietary manipulation, as stated by tion. Although median symptom scores therefore were Barrett et al.,17 but for additional application of XI to quite low in our study, scores for nausea and abdomi- assist in the amelioration of such symptoms.
nal pain were signiﬁcantly improved by XI. There was Isomerisation of fructose by XI may also be useful to no signiﬁcant effect on bloating after administration of avoid high fructose uptake into the body. Further studies XI; however, it has been shown in the past that repro- are required to conﬁrm this hypothesis.
ducibility of symptoms associated with large bowel dila-tation is higher with better characterised symptom of pain as compared with the less speciﬁc symptom of Declaration of personal interests: P. Komericki has served as a speaker for Sciotec Diagnostic Technologies, Tulln, In summary, our proof of concept study has demon- Austria, and M. Akkilic-Materna has received research strated that in patients with incomplete fructose absorp- funding from Sciotec Diagnostic Technologies, Tulln, tion, oral administration of xylose isomerase can reduce Austria. Declaration of funding interests: This study was breath hydrogen excretion in vivo and reduce symptoms funded in full by Sciotec Diagnostic Technologies, Tulln, associated with fructose malabsorption.
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