June 10, 2007
Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Loperamide Plus Simethicone Versus Loperamide Alone and Simethicone Alone in the Treatment of Acute Diarrhea With Gas-Related Abdominal Discomfort
By Hanauer, Stephen B DuPont, Herbert L; Cooper, Kimberly M; Laudadio, Charles
Key words: Abdominal discomfort - Acute diarrhea - Loperamide - Placebo-controlled trial - Randomized controlled trial - Simethicone ABSTRACTObjective: To compare efficacy and tolerabillty of a loperamide/ simethicone (LOP/SIM) combination product with that of loperamide (LOP) alone, simethicone (SIM) alone, and placebo (PBO) for acute nonspecific diarrhea with gas-related abdominal discomfort.
Research design and methods: In this multicenter, double-blind, 48-h study, patients were randomly assigned to receive two tablets, each containing either LOP/SIM 2 mg/125 mg (n = 121), LOP 2 mg (n = 120), SIM 125 mg (n = 123), or PBO (n = 121), followed by one tablet after each unformed stool, up to four tablets in any 24-h period. The primary outcome measures were time to last unformed stool and time to complete relief of gas-related abdominal discomfort. For time to last unformed stool, an unformed stool after a 24-h period of formed stools or no stools was considered a continuance of the original episode (stricter definition) or a new episode (alternate definition).
Results: A total of 483 patients were included in the intent-to- treat analysis. The median time to last unformed stool for LOP/SIM (7.6 h) was significantly shorter than that of LOP (11.5 h), SIM (26.0 h), and PBO (29.4h) (p = 0.0232 in comparison with survival curves) using the alternate definition; it was numerically but not significantly shorter than that of LOP (p = 0.0709) and significantly shorter than that of SIM and PBO (p = 0.0001) using the stricter definition. LOP/SIM-treated patients had a shorter time to complete relief of gas-related abdominal discomfort than patients who received either ingredient alone or placebo (all p = 0.0001). Few patients reported adverse events in the four treatment groups, none of which were serious in nature. Potential study limitations include the ability to generalize study results to the population at large, variability in total dose consumed, and subjectivity of patient diary data.
Conclusions: LOP/SIM was well-tolerated and more efficacious than LOP alone, SIM alone, or placebo for acute nonspecific diarrhea and gas-related abdominal discomfort.
Acute diarrhea is one of the most common diagnoses in general practice1'2, although fewer than 20% of affected individuals actually consult a physician3. It has been estimated that the annual rate of acute diarrhea in industrialized countries averages 0.5 to two episodes per person, per year2. The incidence may be much higher in developing countries4. Acute diarrhea can be defined as the passage of three or more stools per day of looser form than is customary for a period of no longer than 2 weeks2. In most instances, acute diarrhea is accompanied by gas-related abdominal discomfort such as gas pain, cramps, gas pressure, and bloating5. The most common cause of acute diarrhea is a bacterial, viral, or parasitic infection, although some individuals have intolerance to certain foods or medications (e.g., antibiotics, antacids)1'2. The impact of diarrhea is substantial in developing countries, accounting for 2.5 million deaths per year in children younger than 5 years of age4. In the United States, mortality due to diarrhea is essentially confined to the elderly6, although attendance at work or school, professional and personal plans, and travel or vacation plans may be adversely affected.
The management of acute diarrhea may include fluid and salt replacement, dietary alteration, antimicrobial therapy, and symptomatic treatment. Most cases of acute nonspecific diarrhea can be treated with adequate hydration and over-the-counter (OTC) medications3'7. Loperamide hydrochloride (hereafter referred to as loperamide) is the preferred symptomatic treatment for acute diarrhea for most nonfebrile, nondysenteric cases2'8. This agent slows intestinal motility, increases absorption, and reduces secretion, thereby prolonging the transit time of intestinal contents and reducing the loss of fluids and electrolytes9. Loperamide has been available by prescription in Europe and in the USA since the 1970s, and OTC in the USA since 1988. To manage gas- related abdominal discomfort, simethicone, which has been available in many countries since the 1960s, is often used.
In 1997, a chewable tablet containing both loperamide and simethicone became available OTC in the USA for treating the symptoms of acute diarrhea and associated gas-related abdominal discomfort when fever is absent or low grade, dysentery is not present, and there is no blood in the stool. The results of a previously published single-center, randomized, double-blind trial demonstrated that this combination product provided significantly faster relief of acute nonspecific diarrhea and gas-related abdominal discomfort compared with either ingredient alone or placebo over the 48-h study period10. Specifically, loperamide plus simethicone reduced the median time to last unformed stool by 75% compared with placebo, whereas loperamide alone and simethicone alone reduced the same time by only 40% and 17%, respectively, relative to placebo. A 59% reduction in the same endpoint was observed with combination therapy compared with loperamide alone. Similarly, combination therapy reduced the median time to complete relief of gas-related abdominal discomfort by 75% compared with placebo. In contrast, monotherapy with loperamide or simethicone reduced the corresponding time by only 13% and 56%, respectively, versus placebo. These results were unexpected and suggest that loperamide and simethicone may act synergistically to enhance efficacy.
The current multicenter, randomized, double-blind study was designed to compare the tolerability and efficacy of a loperamide and simethicone combination product with the individual components and placebo in the treatment of acute diarrhea with gas-related abdominal discomfort.
The University of Texas Health Science Center at Houston's Committee for the Protection of Human Subjects approved the study protocol, and all study participants gave written informed consent to participate. The study was conducted in accordance with Good Clinical Practice guidelines.
The intent of the study was to examine the effect of treatment across a broad range of acute diarrheal diseases to approximate the setting for anti-diarrheal therapy in a general population such as the USA. Specifically, patients had to meet the following inclusion criteria to participate in the study: (a) were men or women at least 18 years of age (women had to be postmenopausal or using an effective form of contraception for at least 3 months before study entry); (b) had acute diarrheal illness whose symptoms began less than 48 h before study entry; (c) passed at least three unformed stools over the 24 h before study entry; (d) had a most recent bowel movement that was unformed; and (e) had moderately severe or severe gas-related abdominal discomfort (gas pain, cramps, gas pressure, or bloating) during the hour before study entry.
Patients were excluded from the study for the following reasons: (a) diarrheal illness that required hospital admission, outpatient parenteral hydration, or antibiotic therapy; (b) oral temperature greater than 102[degrees]F (39[degrees]C); (c) history or clinical evidence of gross blood or pus in the stool as part of the present illness; (d) history of chronic gastrointestinal disease, hepatic or renal insufficiency, or other significant medical condition that might have been aggravated by untreated acute diarrhea; (e) signs or symptoms of orthostatic hypotension; (f) inability to take fluids and medications by mouth; (g) history of hypersensitivity to loperamide or simethicone; and (h) use of any antibiotic or other drug known to significantly interfere with bacterial flora in the gut within 7 days before study entry, any antidiarrheal or promotility drug or antiflatulent within 12 h before study entry, or any analgesic within 6 h before study entry.
This double-blind, placebo-controlled, outpatient study was conducted at three primary care facilities in Mexico (two in Cancun; one in Puerto Vallarta). Each patient was sequentially assigned to study medication (i.e., numbered vials with attached opaque, sealed envelopes containing the treatment assignment) according to a computer-generated randomization code allocated in blocks of 12. For the first dose of study medication, patients took two chewable tablets of either loperamide/simethicone (each tablet contained 2mg of loperamide/125mg of simethicone), loperamide (each tablet contained 2mg of loperamide), simethicone (each tablet contained 125 mg of simethicone), or placebo in the investigator's office under the observation of study personnel. After the initial dose, patients were instructed to take one tablet after each subsequent unformed stool, up to four tablets in any 24-h period. Each patient was dispensed a total of eight tablets for the 48-h study period. This dosing schedule is consistent with current nonprescription dosing recommendations in the USA for both study medications.
Patients were not to take any other antidiarrheal drugs or antiflatulents wipating in the study. Use of analgesics, antacids, antibiotics, and promotility drugs was also prohibited during the study, and patients were advised to avoid consuming alcoholic beverages, carbonated beverages, nonpotable water, and foods and beverages containing milk or milk products. The choice of rescue medication, if used, was under the discretion of the investigator. Masking
All study medications were identical in appearance and taste, and were provided by McNeil Consumer Healthcare (Fort Washington, PA, USA).
Patients recorded their symptoms, time and consistency of bowel movements, and time of study medication administration for the 48-h period after their initial dose in a daily diary. Patients rated the intensity of their gas-related abdominal discomfort from O (absent) to 4 (severe) hourly over the first 8 h of the study, and at 12, 24, 36, and 48 h after the initial dose and each evening and morning during the study. At the end of the 48 h (or at the time of discontinuation from the study), patients recorded if and when they experienced complete relief from their diarrhea and their gas- related abdominal discomfort (separately), an overall evaluation of the assigned therapy in terms of illness relief, and overall evaluations of the therapy's effectiveness in relieving diarrhea and gas-related abdominal discomfort (separately) on a 5-point categorical scale ranging from O (poor) to 4 (excellent). Adverse events were recorded throughout the study using patient diaries. In these diaries, patients were asked 'Did you experience any unpleasant effects that you believe may have been due to the study medication?' After 48 h in the study and within 72 h of entry, each patient returned to the study site for a second visit at which time the patient diary was returned; at this visit, the entire diary was reviewed with the patient to ensure that all required information had been recorded and any reported adverse events were noted.
The primary efficacy outcome measures were the time to last unformed stool, an objective assessment of the effect of treatment on reducing the duration of diarrheal symptoms, and the time to complete relief of gas-related abdominal discomfort, a subjective assessment of the effect of treatment on the duration of intestinal gas symptoms. Other outcome measures included time to complete relief of diarrhea, end-ofstudy effectiveness, and tolerability.
Two different protocol-specified definitions (stricter definition vs. alternate definition) of the time to last unformed stool were used as there are differing opinions as to what constitutes an episode of diarrhea"'12. The stricter definition used in this study considered an unformed stool after a 24-h period of formed stools or no stools to be a continuance of the original episode. The alternate definition used in this study considered an unformed stool after a 24-h period of formed stools or no stools to be a new episode. Specifically, based on the stricter definition, for patients who completed the study (or discontinued because their diarrhea resolved), time to last unformed stool was the elapsed time from the initial dose to the time of the last unformed stool where only formed stools or no stools were subsequently reported. If no unformed stools were observed, then time to last unformed stool was O. For patients who discontinued for reasons other than resolution of diarrhea, time to last unformed stool was censored at the number of hours from initial dose of study discontinuation. This definition was used previously by Kaplan and colleagues10.
Based on the alternate definition, for patients who completed the study (or discontinued because their diarrhea resolved), time to last unformed stool was the elapsed time from the initial dose to (a) the time of the last unformed stool where only formed stools or no stools were subsequently reported, (b) the beginning of a 24-h stool-free period following unformed stools (any unformed stools occurring after a 24-h stool-free period were taken to be the result of a different episode and were ignored), or (c) if no unformed stools were observed, then time to last unformed stool was O. For patients who discontinued for reasons other than resolution of diarrhea, time to last unformed stool was censored at the number of hours from initial dose of study discontinuation.
A sample size of 480 (120 per treatment group) was deemed sufficient to detect significant differences between treatment group means of at least 7 h at an alpha-level of 0.05 (two-tailed), with a power of 0.80. Sample size estimates were obtained by means of parametric methods applied to pilot data.
All p-values reported in this article are two-sided. Demographic and baseline characteristics were compared among treatment groups using a one-way analysis of variance (continuous variables) or Fisher exact test (dichotomous variables). The treatment groups were compared with respect to the time to relief for each of the primary outcome measures and for time to complete relief of diarrhea using survival analysis techniques13. Patients who prematurely discontinued were censored at the hour of withdrawal from the study. Treatment group differences were evaluated using the Wilcoxon test and log rank test. Because both tests produced comparable results for all evaluations, this article only presents the Wilcoxon test results. The least squares means of the number of stools during each of the four successive 12-h periods during the study were assessed using analysis of variance for repeated measures. End-of-study effectiveness data were assessed using analysis of variance. Fisher exact test was used to compare adverse event rates.
Figure 1. Participant flow
Analyses were performed using an intent-to-treat and per- protocol approach, the latter of which included the subset of patients who adhered to the protocol. Because both approaches produced comparable results for all evaluations, this article only presents the intentto-treat results.
Participant flow and follow-up
A total of 485 patients entered the study between September 1993 and August 1994 (121, loperamide/ simethicone; 120, loperamide; 123, simethicone; 121, placebo). Of the 485 patients who entered the study, 15 discontinued before the end of the 48-h period (Figure 1). The most common reason for discontinuation was receipt of rescue medication (two, loperamide; three, simethicone; and four, placebo).
The intent-to-treat analysis comprised 483 patients. The two patients excluded from the intent-totreat analysis (one, loperamide/ simethicone; one, loperamide) were lost to follow-up.
Demographics and baseline characteristics
Demographics and baseline characteristics were comparable among the four treatment groups, with the exception of a difference in the time from onset of diarrheal illness to the first dose of study medication (p = 0.0073) (Table 1). Overall, 59% of patients were male, 92% were white, and the mean age was 35.4 years. The study included a mixed population of patients with acute diarrhea, including international travelers and local residents. However, detailed information to further define the study population was not collected.
Control of diarrhea
Patients in the loperamide/simethicone group reported significantly faster relief for the primary outcome measure of time to last unformed stool, based on the stricter definition (see Protocol), compared with patients in the simethicone alone (p = 0.0001) or placebo (p = 0.0001) groups (Figure 2); the difference between loperamide/simethicone and loperamide alone, however, was not statistically significant (p = 0.0709). Patients in the loperamide/simethicone group had a reduction of 71% in the median time to last unformed stool compared with patients assigned to placebo, whereas patients assigned to loperamide alone or simethicone alone had reductions in the median time of 59% and 11%, respectively, compared with placebo (Figure 3). When compared with loperamide alone, patients in the loperamide/simethicone group had a 30% reduction in median time to last unformed stool (Figure 3). Based on the stricter definition, a greater percentage of patients in the loperamide/simethicone group (13%) had time to last unformed stool of 0 compared with patients in the loperamide alone (11%), simethicone alone (8%), or placebo groups (3%).
Table 1. Demographic and baseline characteristics by treatment group (all patients)
The time to last unformed stool, based on the alternate definition, was significantly shorter in the loperamide/simethicone group (7.6h) compared with the loperamide alone (11.5h; p = 0.0232), simethicone alone (26.0 h; p = 0.0001), or placebo (29.4 h; p = 0.0001) groups. Patients in the loperamide/ simethicone, loperamide alone, and simethicone alone groups had reductions of 74%, 61%, and 12%, respectively, in the median time to last unformed stool compared with patients assigned to placebo. Using the alternate definition, a greater percentage of patients in the loperamide/ simethicone group (14%) had time to last unformed stool of O compared with patients in the loperamide alone (12%), simethicone alone (8%), or placebo groups (3%).
As shown in Table 2, patients in the loperamide/ simethicone group had significantly fewer unformed stools during each of the 12- h periods compared with patients in the simethicone alone [p =, 0.0282) or placebo (p = 0.0033) groups. In addition, loperamide/ simethicone significantly reduced the number of unformed stools in the first period (> 0-12 h) compared with loperamide alone (p = 0.0447); results favored loperamide/simethicone over loperamide alone during the subsequent 12-h periods, but the differences did not reach statistical significance (Table 2). Over the 48-h study period, greater percentages of patients in the simethicone alone (61%) and placebo (72%) groups passed four or more unformed stools than patients in the loperamide/simethicone (10%) and loperamide alone (18%) groups (Figure 4). In contrast, greater percentages of patients treated with loperamide/ simethicone (78%) and loperamide alone (61%) passed none, one, or two unformed stools than patients in the simethicone alone (26%) and placebo (14%) groups. In comparing the latter two groups of patients treated with combination therapy versus loperamide alone, 78% versus 61% passed none, one, or two unformed stools, respectively, while 23% versus 39% passed three or more stools, respectively. Figure 2. Survival distribution function for time to last unformed stool by treatment group. Loperamide/simethicone vs. loperamide alone, p = 0.0709; loperamide/ simethicone vs. simethicone alone, p = 0.0001; loperamide/ simethicone vs. placebo, p = 0.0001. Results are based on the stricter definition of time to last unformed stool (see Protocol)
Figure 3. Median time to last unformed stool by treatment group. Results are based on the stricter definition of time to last unformed stool (see Protocol)
Figure 5 displays the survival distribution function for the time to complete relief of diarrhea. Pairwise comparisons of the survival curves demonstrate that the time to complete relief of diarrhea was significantly shorter in the loperamide/simethicone group compared with the loperamide alone (p = 0.0292), simethicone alone (p = 0.0001), or placebo (p = 0.0001) groups. The median time to complete relief of diarrhea was 19.6, 23.3, 35.5, and 38.3 h for patients treated with loperamide/ simethicone, loperamide alone, simethicone alone, and placebo, respectively. Compared with placebo, the median time to complete relief of diarrhea was reduced by 49% with loperamide/simethicone, 39% with loperamide alone, and 7% with simethicone alone.
Table 2. Number of unformed stools per 12-h period by treatment group
Figure 4. Percentages of patients who passed unformed stools over the 48-h study period
Figure 5. Survival distribution function for time to complete relief of diarrhea by treatment group. Loperamide/simethicone vs. loperamide alone, p = 0.0292; loperamide/simethicone vs. simethicone alone, p = 0.0001; loperamide/simethicone vs. placebo, p = 0.0001
Relief of gas-related abdominal discomfort
Figure 6 displays the survival distribution function for the time to complete relief of gas-related abdominal discomfort (gas pain, cramps, gas pressure, bloating). Pairwise comparisons of the survival curves demonstrate that the time to complete relief of gas- related abdominal discomfort was significantly shorter in the loperamide/simethicone group compared with the loperamide alone, simethicone alone, or placebo groups (p = 0.0001 for all comparisons). The median time to complete relief of gas-related abdominal discomfort was 12.0, 24.0, 23.2, and 23.5 h for patients treated with loperamide/simethicone, loperamide alone, simethicone alone, and placebo, respectively (Figure 7). Patients in the loperamide/simethicone group had a reduction of 49% in median time to complete relief of gas-related abdominal discomfort compared with patients assigned to placebo, whereas patients assigned to loperamide alone or simethicone alone had negligible changes compared with placebo (Figure 7).
Figure 6. Survival distribution function for time to complete relief of gas-related abdominal discomfort by treatment group. Loperamide/simethicone vs. loperamide alone, p = 0.0001; loperamide/ simethicone vs. simethicone alone, p = 0.0001; loperamide/ simethicone vs. placebo, p = 0.0001
Patients in the loperamide/simethicone group reported significantly higher (improved) least squares means end-of-study values for overall illness relief (2.8), diarrhea relief (2.8), and abdominal discomfort relief (2.8) compared with patients in the loperamide alone (2.4, 2.4, and 2.1, respectively; p =, 0.0052), simethicone alone (2.1, 2.0, and 2.2, respectively; p = 0.0001 for all comparisons), or placebo (1.8, 1.7, and 2.0, respectively; p = 0.0001 for all comparisons) groups. In addition, patients receiving loperamide alone reported a significantly better rating of overall illness and diarrhea relief compared with patients receiving placebo (p = 0.0001 for both comparisons).
Few patients reported adverse events in the four treatment groups (one in the loperamide/simethicone group; zero in the loperamide group; three in the simethicone group; two in the placebo group; p = 0.385). A total of nine adverse events was reported, including nausea (two cases in the loperamide/ simethicone group; one case in the placebo group), fever (one, simethicone; one, placebo), abdominal pain (one, simethicone), dehydration (one, placebo), cramps (one, simethicone), and pruritus (one, simethicone). No cases of constipation were reported. No adverse event was serious. Two patients discontinued the study because of adverse events: one patient in the simethicone group for abdominal pain, which was considered by the investigator to be possibly related to study medication, and one patient in the placebo group for dehydration.
Figure 7. Median time to complete relief of gas-related abdominal discomfort by treatment group
These data demonstrate that the combination of loperamide and simethicone provided faster relief of acute nonspecific diarrhea and associated gas-related abdominal discomfort (gas pain, cramping, gas pressure, and bloating) beyond that achieved with either ingredient alone or placebo. The median time to last unformed stool for the combination of loperamide and simethicone was faster by a range of approximately 4-22 h versus the comparators. Faster relief of diarrhea may increase patient satisfaction and allow resumption of patient activities in a timely manner. The results were clinically significant across all primary and secondary measures of efficacy and statistically significant for all but the comparison between loperamide/simethicone and loperamide alone based on the stricter definition of time to last unformed stool. Importantly, loperamide/ simethicone was better than loperamide alone or placebo in reducing the number of stools within the initial 12 h of the study. In acute diarrhea, this is the time period when a drug would be expected to be effective; symptomatic improvement generally occurs thereafter, such that differences between active treatment and placebo would no longer be apparent. The data also showed that there were no withdrawals associated with the need for rescue medication in the loperamide/simethicone group, and that all study medications were generally well-tolerated. Similar observations were reported previously10, further strengthening the conclusions of this randomized controlled trial.
Mechanism of action and pharmacokinetic studies may provide a rationale for our clinical findings and those of Kaplan and colleagues10 but, to date, few have been published. Connor and colleagues conducted a two-way, randomized, crossover scintigraphic study in which 12 healthy volunteers received radiolabeled loperamide/simethicone chewable tablets and loperamide capsules after an overnight fast14. On average, administration of the combination product was associated with a 33% increase in the time for half of the radioactivity to empty from the stomach compared with loperamide capsules, a 27% increase in the time for half of the radioactivity to arrive in the colon, and a 22% increase in residence time in the small intestine. Although the differences did not reach statistical significance, these trends indicate that in some individuals treated with the combination, study medication progressed more slowly through the gastrointestinal tract, which may result in increased pharmacologie activity. Of note, scintigraphic images revealed substantial coating of the jejunum-proximal ileum between 1 and 2 h after dosing with the combination product14. The authors speculated that this was probably due to simethicone lining the mucosal surface, which in turn may have increased the availability of loperamide at the intestinal receptors that mediate its antidiarrheal activity. These data provide some evidence to suggest that the enhanced antidiarrheal effects of the loperamide/ simethicone combination product may be attributable to alterations in the intestinal kinetics of loperamide. It would be interesting and perhaps more relevant to assess the same kinetics in the hypersecretory state characteristic of diarrhea.
In the present study, simethicone alone did not demonstrate efficacy on the primary measure of gas-related symptom relief, which was median time to complete relief of gas-related abdominal discomfort. However, when simethicone was given concomitantly with loperamide, the same outcome was reduced by nearly 50% compared with placebo. Similarly, at the end of the study, patient ratings of relief of abdominal discomfort yielded only 10% improvement with simethicone when compared with placebo, whereas 40% improvement was reported with loperamide/simethicone. A possible explanation for this outcome is that loperamide-induced decreases in intestinal motility and secretion and increases in fluid reabsorption may have enhanced the ability of simethicone to coalesce gas by prolonging contact time on a lower volume of intestinal fluid. Interestingly, in a previous study, simethicone alone substantially reduced the median time to complete relief of gas-related abdominal discomfort by 56% versus placebo and improved patient-rated relief of abdominal discomfort by more than two-fold10. The reason for the disparity between the two studies is unclear, but does not appear to be related to differences in the patient populations.
As with any clinical trial, there were a number of possible limitations that are worth noting. First, one could possibly challenge the degree to which the study population represented the population at large. We intentionally enrolled a combination of international travelers and local residents, because we believed this would reasonably approximate the typical US population that would use a nonprescription antidiarrheal product to control the symptoms of acute diarrhea, including travelers' diarrhea. However, non-white individuals and individuals under the age of 18 probably were not well represented in our study population. second, because subjects were instructed to take one tablet after each unformed stool following the initial two-tablet dose, the total dose consumed probably was not uniform across all subjects. However, this dosing regimen was consistent with the product labeling, as well as with dosing regimens used in other studies of antidiarrheal therapy. In addition, one would expect the randomization process to evenly distribute this variability across the treatment groups. Finally, data were collected using patient diaries, which might have introduced an element of subjectivity into the assessment of stool consistency and other parameters. However, this method of data collection is widely accepted in studies of antidiarrheal therapy and, as with the total dose consumed, one would expect the randomization process to evenly distribute any variability across the treatment groups. Conclusion
In summary, the results of this multicenter, randomized, double- blind, placebo-controlled study indicate that the combination of loperamide/simethicone was well-tolerated and more efficacious than loperamide alone, simethicone alone, or placebo in the treatment of acute nonspecific diarrhea and associated gas-related abdominal discomfort.
Declaration of interest: This study was supported by McNeil Consumer Healthcare. SBH has served as a consultant to McNeil Consumer Healthcare. HLD has received an honorarium and research grants (via his university employment) from McNeil Consumer Healthcare; he also is on the speaker's bureau for and has received grants (via his university employment) from Salix Pharmaceuticals. KMC is an employee of McNeil Consumer Healthcare. CL was an employee of McNeil Consumer Healthcare at the time of this study. The authors acknowledge Thomson Scientific Connexions for editorial support in preparation of this manuscript.
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-3745_3, Accepted for publication: 20 February 2007
Published Online: 26 March 2007
Stephen B. Hanauer(a), Herbert L. DuPont(b), Kimberly M. Cooper(c) and Charles Laudadio(c)
a University of Chicago, Chicago, IL, USA
b St. Luke's Episcopal Hospital, University of Texas-Houston School of Public Health, and Bay/or College of Medicine, Houston, TX, USA
c McNeil Consumer Healthcare, Fort Washington, PA, USA
Address for correspondence: Stephen B. Hanauer, MD, Professor of Medicine and Clinical Pharmacology, Chief, section of Gastroenterology and Nutrition, University of Chicago, 5841 S. Maryland Ave., MC 4076, Chicago, IL 60637, USA. Tel.: +1 773 834 7308; Fax: +1 773 702 2182; [email protected]
Copyright Librapharm May 2007
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