Andrea Allen Ph.D. EDUCATION B.A., 1971, Washington Square College, New York University Ph.D., 1976, Psychology (Social & Personality), Stanford University PSYCHOLOGY POSITIONS (New York State Licensed Psychologist, #012971) Mount Sinai Medical Center, Mount Sinai School of Medicine, New York, New York Assistant Clinical Professor of Psychology in Psychiatry, July 2009 to pr
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Ajg_50255.texIntravenous Iron Sucrose versus Oral Iron Supplementationfor the Treatment of Iron Deficiency Anemia in Patientswith Inflammatory Bowel Disease—A Randomized,Controlled, Open-Label, Multicenter StudyOliver Schr¨oder, M.D.,1 Oliver Mickisch, M.D.,2 Ursula Seidler, M.D.,3 Andreas de Weerth, M.D.,4 Axel U.
Dignass, M.D.,5 Hans Herfarth, M.D.,6 Max Reinshagen, M.D.,7 Stefan Schreiber, M.D.,8 Ulrich Junge, M.D.,9Marc Schrott, PharmD.,1 and J¨urgen Stein, M.D., Ph.D.11First Department of Internal Medicine, Division of Gastroenterology, ZAFES, Johann WolfgangGoethe-University, Frankfurt, Germany; 2Private Gastroenterology Practice, Mannheim, Germany;3Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover,Germany; 4Department of Medicine, University Hospital Eppendorf, Hamburg, Germany; 5Charit´e MedicalSchool-Virchow Clinic, Department of Medicine, Division of Hepatology and Gastroenterology, Berlin,Germany; 6Department of Internal Medicine I, University of Regensburg, Regensburg, Germany;7Department of Medicine I, University of Ulm, Ulm, Germany; 8First Department of Medicine,Christian-Albrechts-University, Kiel, Germany; and 9Municipal Hospitals Bielefeld, Hospital Rosenh¨ohe,Bielefeld, Germany Anemia is a frequent complication in patients with inflammatory bowel disease (IBD). The optimalroute for iron supplementation to replenish iron stores has not been determined so far. We thereforeevaluated the efficacy and safety of intravenous iron sucrose as compared with oral iron sulfate forthe treatment of iron deficiency anemia (IDA) in patients with IBD.
A randomized, prospective, open-label, multicenter study was performed in 46 patients with anemiaand transferrin saturation ≤20% and/or serum ferritin concentrations ≤20 µg/L. The intravenousgroup received a single dose of iron sucrose of 7 mg iron/kg body weight, followed by five 200 mginfusions for the following 5 wks. The oral group received iron sulfate 100–200 mg per day for 6 wks.
While a comparable increase in hemoglobin was observed for both administration routes (medianincrease 0.25 g/L in the intravenous group vs 0.21 g/L in the oral group), only iron sucrose led to arise in serum ferritin concentrations. Intractable gastrointestinal adverse events caused permanentstudy drug discontinuation in five patients (20.8%) receiving iron sulfate, whereas only one patient(4.5%) had to be withdrawn because of side effects due to iron sucrose.
CONCLUSIONS: Although being equal in short-term efficacy and overall tolerability our results suggest a better gastrointestinal tolerability for iron sucrose. Larger trials are mandatory to prove a possibleadvantage of iron sucrose in short- and long-term efficacy as well as in tolerability over iron sulfate inthe management of IDA in IBD.
(Am J Gastroenterol 2005;100:2503–2509) INTRODUCTION
loss from the gut, suppression of erythropoietin production,and alteration of iron metabolism by proinflammatory cy- Iron deficiency anemia (IDA) is a frequent complication in tokines, reactive oxygen metabolites, and nitric oxide (for inflammatory bowel disease (IBD), with a prevalence rang- ing from 17% to 70% (1–4). It has significant impact on the Until recently, oral iron supplementation has been the quality of life (QoL) in affected patients. IDA is not only char- mainstay therapy for anemia in IBD. However, this treat- acterized by a higher score of disease activity, loss of weight, ment is limited by poor absorption and frequent side ef- and impaired physical activity but also by developmental and fects, thereby straining resources of clinicians and challeng- cognitive abnormalities in children and adolescents (5). The ing the patient’s compliance (7, 8). Moreover, there is a legiti- causes of IDA in IBD are thought to include chronic blood mate concern that oral iron may exacerbate inflammation and oder et al.
tissue damage by hydroxyl radicals formed from hydrogen 100-200 mg/d
Group B (PO group)
peroxide via the Fenton reaction (9, 10). Indeed, there is ev-idence that iron supplementation induces inflammation both Group A (IV group)
in normal rats and in rodent models of IBD (11–13). In ad-dition, dietary iron has been shown to enhance colorectalcarcinoma development in an ulcerative colitis (UC) mouse During the last few years, experience in the use of intra- venous iron sucrose in various forms of IDA including IBD Screening
has been evolved. Gasch´e et al. could demonstrate the effi-cacy of such form of iron supplementation (3, 15, 16). We Figure 1. Schematic diagram of the study design.
recently published promising results regarding the safety andtolerability of an intravenous high-dose iron sucrose therapy(7 mg iron per kg body weight) in IBD patients with IDA wks prior to screening, a serum ferritin concentration >300 (17). Iron sucrose is a water-soluble compound composed of µg/L, hemolysis with haptoglobin <50 mg/dL, renal insuf- a polynuclear iron (III) hydroxide inner sphere surrounded ficiency (serum creatinine >1.2 mg/dL), suspicion of hy- by sucrose molecules. This complex has a molecular mass poplastic bone marrow failure states or hematologic malig- of approximately 52 kDa and is therefore excreted only to a nancy, pregnancy, lactation or the use of inadequate forms of low extent through the renal pathway (18). The intravenously birth control, severe concurrent illness, and participation in a administered iron complex is stable in the blood circulation clinical trial within the last 1 month. Furthermore, no blood and cleared with a half-life of 5–6 h. The iron complex is transfusion or parenteral iron infusion was permitted for at rapidly distributed to the bone marrow for erythropoiesis and the reticuloendothelial system of the liver and the spleen forstorage of iron. Iron deposition in hepatocytes is negligible Assignment
and thus liver toxicity is prevented. Moreover, in contrast Patients were randomized using a computer-generated ran- to iron dextran, antibodies to iron sucrose do not occur (for The most appropriate route for iron supplementation in pa- Participant Flow and Follow-Up
tients with IBD has not been determined so far. We therefore Patients were assigned to the following two treatment groups examined for the first time the short-term efficacy and toler- (Fig. 1): group A received a loading dose of iron sucrose ability of oral and intravenous iron in IBD in the setting of (Venofer , Vifor Int., St. Gallen, Switzerland) of the max- a randomized, controlled, open-label multicenter study, com- imal recommended concentration of 7 mg/kg body weight paring outcomes in patients receiving either intravenous iron administered as a drip infusion over 3.5 h in 0.9% sodium chloride at visit 1. Thereafter, iron sucrose in a dose of 200mg iron was infused over 30 min one to two times weekly dur-ing 5 wks in a fixed schedule. Patients in group B received oral iron sulfate (ferro sanol duodenal, Sanol GmbH, Mon- Protocol
heim, Germany) 100–200 mg per day for 6 wks, depending The study was a randomized, controlled, open-label, multi- on the discretion of the attending physician. The primary end center, clinical trial carried out in accordance with the princi- point was the determination of the maximum change in Hb ples enunciated in the Declaration of Helsinki. The study was from baseline to week 6 visit. Secondary end points com- approved by the local ethical committees of the participating prised of a safety comparison of adverse events between the clinical centers and monitored by PAREXEL-PACE, Berlin, two study arms, the change in QoL, as well as changes in Patients with IBD were identified through clinic registra- Biologic monitoring was carried out at distinct visits. At tion records at the participating nine primary care sites from study entrance (1–7 days before start of treatment), medi- August 2003 until March 2004. Patients with an IDA as de- cal history, concomitant medication and IBD activity scores fined by a hemoglobin (Hb) concentration of ≤1.05 g/L (fe- were recorded and blood was collected for determination of males) or Hb ≤1.10 g/L (males) plus a transferrin satura- hematological (Hb, Hct, MCV, WBC count, reticulocytes) tion (TSAT) ≤20% and/or serum ferritin concentrations ≤20 and clinical chemistry parameters including a pregnancy test, µg/L were eligible to the study. Inclusion criteria included ferritin, iron, transferrin, TSAT, vitamin B12, folic acid, cre- informed consent and age of 18–85 yr.
atinine, haptoglobin, C-reactive protein, AST, and ALT. At Patient exclusion criteria included anemia not attributable the beginning of treatment, patients were randomly assigned to iron deficiency, iron overload or disturbances in the uti- to either study group and concomitant medication, physical lization of iron, known hypersensitivity to iron mono- or dis- examination including body weight, vital signs (heart rate, accharide complexes, use of erythropoietin within the last 2 blood pressure), adverse events, and QoL were recorded. At Intravenous Iron Sucrose versus Oral Iron in IBD
week 1, 2, 4, and 5 concomitant medication, vital signs, and Table 1. Baseline Demographic Data of the Study Patients
adverse events were monitored. In addition, at week 3 and 6 of the study laboratory tests including hematology and clini- cal chemistry (ferritin, iron, transferrin, and TSAT at week 3; ferritin, iron, transferrin, TSAT, creatinine, haptoglobin, C- reactive protein, AST, and ALT at week 6) were performed.
Also, IBD activity scores (week 3 and 6) and QoL (week 6) MEASUREMENTS OF IRON INDICES, CLINICAL ACTIVITY
INDICES, AND QoL
Transferrin and ferritin were measured by nephelometry (BN 40 Nephelometer, Dade Behring, Liederbach, Germany), and plasma iron was determined colorimetrically by using stan- dard methods as recommended by the ICSH iron panel (20).
TSAT was calculated from serum iron and transferrin (serum QoL was assessed by using the 36-item short-form (SF- 36). The SF-36 includes one multi-item scale evaluating eight health dimensions: physical functioning, role limitations due to physical health problems, role limitations due to emotional Active disease is defined by a CDAI >150 (MC) or a CAI >4 (CU); the status of remission is classified as a CDAI ≤150 (MC) or CAI ≤4 (CU).
problems, social functioning, bodily pain, mental health, vi-tality, and general health perceptions (21).
In order to validate the clinical activity of UC, the colitis activity index (CAI) according to Rachmilewitz et al. was Baseline Data
applied (22). This index is calculated as the sum of the total From the 46 patients enrolled into the study, 22 were randomly scores of seven variables: number of stools, percentage of assigned to receive intravenous iron sucrose (group A), while bloody stools, abdominal pain, general well-being in the last 24 patients were allocated to receive oral iron (group B). On 7 days, temperature due to UC, presence of extraintestinal inclusion, both treatment groups were comparable with re- manifestations, and laboratory findings (ESR, Hb). To assess spect to biological and clinical data (Table 1). The baseline the therapeutic effect of the treatment for Crohn’s disease Hb concentration was similar for both groups (0.98 g/L in (CD), the Crohn’s disease activity index (CDAI) was used.
group A vs 0.96 g/L in group B). Both groups displayed sub- This index comprises a scoring system including the number stantial reduction in serum ferritin concentrations (12 µg/L of liquid stools, abdominal pain, and the general well-being in group A vs 8 µg/L in group B and TSAT (6.5% in group in the last 7 days, presence of extraintestinal manifestations, A vs 5.5% in group B), both indicating IDA. Additional iron usage of antidiarrhoica, physical examination (presence of an metabolism-related parameters are presented in Table 2.
abdominal mass), laboratory findings (hematocrit), and body Although not statistically significant, both groups rather differed in the distribution of IBD entity: group A consistedof 17 patients with CD and 5 patients with UC; group B wascomposed of each 12 CD and 12 UC patients. However, with Statistical Analysis
respect to disease activity and concomitant medication both Due to the small number of the two study groups results are groups were similar. At the time of inclusion, most patients expressed as median and interquartile range if not otherwise (16 out of 22 patients in group A vs 20 out of 24 patients in indicated. Because the spread of results was not normally dis- group B) had active disease as determined by the respective tributed, non-parametric tests were used in the statistical anal- disease activity score. The baseline CDAI were 217 (group ysis of data, namely the Mann-Whitney test for comparisons A) versus 281 (group B); the baseline CAI were assessed to of non-paired series, and the Wilcoxon test for comparisons be 11 (group A) and 8 (group B), respectively.
of paired series. For qualitative data, two-sided Fisher’s exacttest was applied. Variations of p < 0.05 or less were con- Outcome Data
sidered to be statistically significant. Statistical analysis was Eighteen out of 22 patients (81.8%) in the intravenous iron performed using the Jandel Sigma Stat 2.0 software package group and 17/24 patients (70.8%) in the oral iron group completed the study. Reasons for not completing the study oder et al.
Table 2. Iron Metabolism-Related Parameters During the Course of the Trial
∗p < 0.001 for comparison between the two groups.
were protocol violation (N = 1), withdrawal of consent (N statistically significant difference in serum ferritin concentra- = 1), and adverse events (N = 2) in group A, while adverse tions between both groups was observed: group A showed a events (N = 5), withdrawal of consent (N = 1), and protocol strong increase in serum ferritin concentration at week 3 and violation (N = 1) were the cause for not completing the trial 6, whereas in patients of group B there was only a negligible trend toward increasing ferritin values (Fig. 3).
There was a highly statistically significant difference in No clinically relevant nor statistically significant changes administered iron between both groups: the overall dosage of in vital signs (blood pressure and heart rate) as well as in liver iron in patients assigned to receive intravenous iron sucrose and kidney function tests were noted in both groups during amounted to a median dosage of 1,418 mg (1,375–1,452 mg).
the study period (data not shown). In the same manner, no In group B, 16/24 (66.7%) patients received 100 mg oral iron statistical changes could be notified for C-reactive protein as sulfate daily, whereas 8/24 (33.3%) patients were treated with a variable for monitoring the inflammatory status. In patients 200 mg oral iron per day, accounting to a median total dosage receiving parenteral iron, median serum C-reactive protein of 4,200 mg (4,200–8,400 mg), e.g., three times the intra- concentrations were 5.5 mg/L (1.3–16.0 mg/L) at baseline venous dose ( p < 0.001). At the level of the total medium and 8.5 mg/L (2.9–23.0 mg/L) at the end of the study ( p = iron supplementation, the divergence was even more pro- 0.54); the respective values for the patients treated with oral nounced (1,418 mg in group A vs 5,600 mg in group B). Due iron supplementation were 8.5 mg/L (2.8–22.5 mg/L) at the to the difference in cumulative dose of administered iron allfollowing data regarding the efficacy and safety between bothstudy groups do not allow for a direct comparison betweenboth study groups.
With the exception of a single patient receiving parenteral iron all other 34 patients completing the study experienced an P = 0.000001
increase in Hb to the respective treatment during the course P = 0.000002
of the study. The median rise after 6 wks totaled 0.25 g/L (0.15–0.29 g/L) for group A and 0.21 g/L (0.12–0.27 g/L) for group B, respectively (Fig. 2). As demonstrated in Table 2, the two groups showed no differences in Hb concentration at any time. The cumulative response rate as defined as anincrease in Hb concentration of 0.2 g/L or more was also com- P = 0.0005
parable for both groups (55% in group A vs 53% in group B, p = 0.85). Corpuscular volume, hematocrit, serum iron, and TSAT also increased similarly in both groups. Reticulocyte baseline wk 3 wk 6
baseline wk 3 wk 6
count rose transiently in the parenteral iron group, whereas in (n=22) (n=18) (n=18)
(n=24) (n=17) (n=17)
patients, receiving oral iron sulfate a trend toward a decrease Figure 2. Changes in hemoglobin concentration in response to in-
in reticulocytes over time was noted. However, the difference travenous iron sucrose (white boxes) versus oral iron sulfate (gray was not statistically significant. Serum transferrin concentra- boxes). Boxes represent median and interquartile range, error bars tions remained constant during the study phase. In contrast, a Intravenous Iron Sucrose versus Oral Iron in IBD
Table 4. Course of IBD Activity Indices During the Course of the
P = 0.0003
P = 0.0004
Data are median with the range in parenthesis; p for comparison of baseline to week 6.
( p = 0.19). This patient suffered from immediate nausea, baseline wk 3 wk 6
baseline wk 3 wk 6
facial rash and peripheral oedema during the cause of the (n=22) (n=18) (n=18)
(n=24) (n=17) (n=17)
first iron sucrose infusion. Symptoms resolved within 2 h of Figure 3. Changes in serum ferritin concentration in response to
immediate discontinuation of the infusion. In addition, one intravenous iron sucrose (white boxes) versus oral iron sulfate (gray patient experienced a phlebothrombosis of the right femoral boxes). Boxes represent median and interquartile range, error bars vein 8 days after the first parenteral iron administration. Al- though the relation of this serious adverse event to the studydrug was considered unlikely, the patient was discontinued beginning and 9.1 mg/L (2.6–20.5 mg/L) at the end of the As can be deduced from Table 4, both IBD activity indices The adverse event profile is displayed in Table 3. A total decreased in either group during the course of the study, thus of 41 adverse events were observed in 21 patients, of which indicating clinical improvement. These changes were accom- 11 patients belonged to group A and 10 patients to group B.
panied by an increase of the number of patients with inactive Almost half of the adverse events ranked among gastroin- disease at the end of the study. Only five patients (27.8%) in testinal disorders, such as nausea and vomiting, abdominal group A and four (23.5%) in group B completing the study pain, flatulence, and diarrhoea, of which in turn the vast ma- had active disease after 6 wks of treatment as determined jority emerged in the group receiving oral iron supplementa- by CDAI and CAI, respectively. Accordingly, a trend toward tion. In fact, the occurrence of abdominal pain between both reduced systemic corticosteroid therapy could be observed groups was even found to be borderline significant. Moderate in both treatment groups during the study period. The pred- to severe gastrointestinal adverse events, which all occurred nisolone dosage dropped from 30.2 mg per day (15.0–50.0 within a week after the start of iron sulfate, led to a perma- mg per day) at baseline to 22.0 mg per day (10.0–30.0 mg nent study drug discontinuation of five patients in group B.
per day) after 6 wks in group A ( p = 0.24) and from 28.3 mg In contrast, only one patient of group A dropped out from per day (9.4–42.5 mg per day) to 16.7 mg per day (5.0–22.5 further study due to adverse events related to iron sucrose mg per day) in group B ( p = 0.06), respectively. No signifi-cant difference between both treatment arms with respect toprednisolone tapering could be found.
Table 3. Profile of Observed Adverse Events During the Study
In contrast to the clinical activity indices, QoL was not affected during the course of the study, although in both groups a trend toward increased SF-36 scores was noted: 104.5 (95.0–113.5) at baseline versus 108.0 (100.0–116.5) at the end of the study (group A) and 111.0 (105.0–116.5) at baseline versus 116.0 (108.0–120.0) at study completion for DISCUSSION
For many years, it has been common clinical practice to man- age IDA by oral iron supplementation. This has also been adopted in the latest guideline of the British Society of Gas- troenterology (24). In contrast, parenteral iron is only rec- ommended when there is intolerance to oral preparations or noncompliance. However, gastrointestinal side effects (e.g., ∗Edema or tenderness at the intravenous administration site.
nausea, bloating, diarrhoea, or upper gastrointestinal pain), oder et al.
which are the most common reasons for discontinuation of iron treatment arm the oral iron supplementation would have medication, are even more pronounced compared with those had to some degree be even larger (or the cumulative dose of observed in non-IBD patients taking oral iron therapy (25).
intravenous iron sucrose even smaller) to allow for a direct Moreover, in contrast to intravenous iron sucrose oral iron comparison of efficacy and safety parameters.
has also been observed clinically to produce disease exac- Apart from efficacy, our study intended to compare safety erbations (10, 26). These observations in a small number of and tolerance of the two iron administrative pathways in IBD.
patients are supported by findings in several rodent models While the total amount of adverse events was comparable in of colitis demonstrating an aggravation of the inflammatory both groups, their types differed: 15 out of 21 (71.4%) ad- status during the course of oral iron supplementation. In addi- verse events observed in the group receiving oral iron ther- tion, iron chelators were shown to ameliorate oxidative stress apy could be attributed to gastrointestinal disorders, whereas and inflammation in colitic rats (27) and colonic biopsies adverse events of such clinical category occurred in a fre- (28) from patients with UC. These detrimental effects are quency of only 10% in the group treated with intravenous thought to be related to increased oxidative stress. Mouse iron sucrose (p < 0.001). Furthermore, solely gastrointesti- model data further suggest that oral iron supplementation nal side effects caused a permanent drug discontinuation in may contribute to the carcinogenesis process in IBD by aug- five patients supplemented with oral iron sulfate. Concerning menting oxidative damage and inflammation-caused epithe- the overall tolerability no statistically significant difference lial proliferation (14). The majority of the tumors observed between both treatment arms could be found. Nevertheless, in this rodent model were well-differentiated, mucinous ade- as already discussed above, if comparable bioavailable iron nocarcinomas, the most commonly found type of carcinoma doses had been applied in this study, an even more favorable in patients with UC. Again, colorectal tumor incidence was safety outcome for intravenous iron sucrose could be antici- significantly reduced in mice consuming the iron chelator pated. Since its introduction in the European market in 1950 iron sucrose has compiled a consistent safety record. The With this background in mind, this randomized controlled experience reported in clinical trails and the experience ac- trial was conducted to compare for the first time the efficacy quired over the years of its use in clinical practice confirmed and tolerance of intravenous iron sucrose and oral iron sup- its safety (19). The preference of oral iron over other admin- plementation for the treatment of IDA in patients with IBD.
istrative pathways as the iron supplementation of choice to Our data clearly demonstrate that both routes of iron ad- compensate IDA has also been established on the cheap cost ministration yield to an excellent therapy response in the of iron sulfate. However, taken the high incompliance of oral management of IDA in IBD. All but one of the 34 patients intake due to intolerance into account, it might be interesting completing the study experienced a rise in Hb concentra- to investigate which of the two forms of iron supplementation tions. This patient with UC suffered from continuous rectal may prove to be more cost-effective in pharmacoeconomics bleeding despite escalating immunosuppressive medication.
Therapeutic response of oral and parenteral iron developed In contrast to tolerability, both administrative pathways uniformly with statistically significant increase in Hb concen- demonstrated equal safety with respect to other evaluated trations for both administrative pathways already after 3 wks safety parameters. Neither vital signs such as heart rate or of treatment. In half of the patients of either treatment group a blood pressure nor liver and kidney laboratory function tests rise of the Hb concentration ≥0.2 g/L was observed. In addi- were negatively affected by either treatment regimen. In addi- tion, with the exception of the above mentioned refractory UC tion, no significant changes in serum levels of the C-reactive patient no dependence of therapeutic response of both regi- protein could be detected in either group, whereas disease ac- mens was noticed with respect to disease activity. However, tivity as determined by CDAI and CAI improved to the same this assumption has to be interpreted with caution because extent in both groups. However, since most patients included of the relatively small study population. In accordance with in the study had active disease, the observed positive effects recently published data comparing both iron administrative were not only a result of correcting IDA, but more likely pathways in IDA of pregnancy (30) a strong—although with evoked by the concomitant immunosuppressive medication a large variation—increase in serum ferritin concentration was noted in patients receiving iron sucrose, while there was In conclusion, the results of our randomized, controlled, only a negligible trend toward increasing concentrations in open-label, multicenter study prove for the first time the equal the oral iron group. The reason for the lack of increment in short-term efficacy of intravenous iron sucrose and oral iron serum ferritin in patients receiving iron sulfate as compared supplementation for the treatment of IDA in patients with with iron sucrose is most likely due to an actual lower amount IBD. Our safety data further suggest that iron sucrose has of bioavailable iron in the oral treatment arm: intestinal ab- a better gastrointestinal safety profile that might positively sorption of iron usually occurs at a rate of ∼10%, which in influence the compliance, especially in IBD patients. Never- this case is further decreased to some extent as a consequence theless, we have to acknowledge that the small sample size of of the underlying inflammatory status and the so-called mu- the enrolled patients resulted in a study underpowered to de- cosa block phenomenon of preceding iron doses (31). Thus, tect differences in both, the efficacy and overall tolerability despite a fourfold higher mean cumulative dose in the oral of both iron administration routes. Thus, larger trials also Intravenous Iron Sucrose versus Oral Iron in IBD
addressing other important topics, such as bioavailability is- inflammatory cytokines in IL-10 deficient mice. Eur J Clin sues, long-term effects, or influence of disease activity, are mandatory to verify an advantage of intravenous iron sucrose 12. Carrier J, Aghdassi E, Platt I, et al. Effect of oral iron supplementation on oxidative stress and colonic inflamma- compared with oral iron supplementation in the management tion in rats with induced colitis. Aliment Pharmacol Ther 13. Uritski R, Barshack I, Bilkis I, et al. Dietary iron af- fects inflammatory status in a rat model of colitis. J Nutr ACKNOWLEDGMENTS
14. Seril DN, Liao J, Ho KL, et al. Dietary iron supplementation J.S. was senior author, principal investigator, and trial coor- enhances DSS-induced colitis and associated colorectal car- dinator. O.M., U.S., Ad.W., A.D., H.H., M.R., S.S., and U.J.
cinoma development in mice. Dig Dis Sci 2002;47:1266–78.
were co-investigators. O.S. was responsible for data analysis 15. Gasch´e C, Dejaco C, Reinisch W, et al. Sequential treatment and writing the draft of the manuscript. M.S. undertook the of anemia in ulcerative colitis with intravenous iron and data collection. All authors contributed to the final version erythropoietin. Digestion 1999;60:262–7.
16. Gasch´e C, Dejaco C, Waldhoer T, et al. Intravenous iron of the manuscripts. There was no conflict of interest for any and erythropoietin for anemia associated with Crohn dis- of the authors. This study was sponsored by Vifor Int., St.
ease. A randomized, controlled trial. Ann Intern Med Gallen, Switzerland. Additional support came from the Else 17. Schr¨oder O, Schrott M, Blumenstein I, et al. A pilot study for Dedicated to Professor Wolfgang F. Caspary on the occa- the evaluation of safety and tolerability of intravenous high-dose iron sucrose in patients with iron deficiency anemia due to gastrointestinal blood loss. Z Gastroenterol 2004;42:663–7.
Reprint requests and correspondence: Oliver Schr¨oder, M.D.,
18. Danielson BG, Salmonson T, Derendorf H, et al. Pharma- First Department of Internal Medicine, ZAFES, Johann Wolfgang cokinetics of iron(III)-hydroxide sucrose complex after a Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt Main, single intravenous dose in healthy volunteers. Arzneimit- Received February 15, 2005; accepted June 7, 2005. 19. Yee J, Besarab A. Iron sucrose: The oldest iron therapy be- comes new. Am J Kidney Dis 2002;40:1111–21.
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Nebulisers Nebulisers You should only use a nebuliser if your doctor has advised you to do so. This information sheet is designed for people already using a nebuliser and is only intended to be used as a guide. You should always discuss the use of your medicines with your doctor or nurse. A nebuliser is a powerful drug delivery system. It should only be used if your doctor has