Evaluation of safety and efficacy of the combination of mebeverine and sulpiride in treatment of patients with functional gastrointestinal disorders: A prospective cohort

Abstract

Objective

In this study, we aimed to evaluate the safety and efficacy of a combination of 100 mg mebeverine and 25 mg sulpiride (Colona®) in patients with functional gastrointestinal disorders.

Methods

This multicenter, cohort study was conducted in Egypt, comprising 253 patients diagnosed with functional gastrointestinal disorders. The treatment duration was 2 weeks. The primary endpoint was the percentage of relative change in the tailored gastrointestinal symptoms rating scale.

Results

The baseline tailored gastrointestinal symptoms rating scale mean (±SD) score was 11.42 ± 4.10. However, after 2 weeks (±1 week) of combination therapy, the score significantly decreased to 3.11 ± 2.48 (p < 0.01), demonstrating a mean (±SD) improvement of 71.84% ±20.56%. Among 253 patients, 227 patients (89.72%, 95% confidence interval: 85.96%–93.49%) demonstrated ≥50% improvement in the tailored gastrointestinal symptoms rating scale total score, whereas 26 (10.28%) did not report any improvement. In terms of safety, 2 (0.79%) patients reported diarrhea, 1 (0.4%) had mild dyspepsia, and 1 (0.4%) had galactorrhea.

Conclusion

Our results suggest that the combination of mebeverine and sulpiride may represent a safe and effective treatment option for patients with functional gastrointestinal disorders.

Keywords

Functional gastrointestinal disorders abdominal pain quality of life mebeverine sulpiride

Background

Functional gastrointestinal disorders (FGIDs) comprise a group of diverse chronic disorders resulting from altered brain–gut communication in the absence of structural or biochemical deviations corresponding to the experienced symptoms. These symptoms may include dyspepsia, dysphagia, diarrhea, constipation, bloating, and abdominal pain.^1,2 According to the International Foundation for Gastrointestinal Disorders (IFFGD), functional dyspepsia (FD) is a condition characterized by symptoms originating in the upper digestive tract without structural or metabolic abnormalities.³

A relationship exists between FGIDs, psychosocial and physiological factors, and clinical outcomes. Environmental and psychological factors early in life can considerably affect the individual’s susceptibility to gastrointestinal (GI) dysfunction, including impaired motility, visceral hypersensitivity, or weakened mucosal immunity.³ The most widely known GI dysfunctions include irritable bowel syndrome (IBS), FD, and functional constipation.⁴ The absence of a defined pathology and specific biomarkers makes the diagnosis of FGIDs challenging for clinicians. Consequently, symptom-based diagnosis is used to distinguish and treat each condition. The new Rome III classification was established to enhance the knowledge and clinical management of FGIDs by categorizing symptoms into clusters that are constant across populations. The criteria subclassifies FD into epigastric pain syndrome and postprandial distress syndrome, according to meal-related symptoms. These modifications may cause changes in the estimated prevalence of each subtype and the patient selection for clinical trials.³

FGIDs are a major public health concern because they are extremely common, disabling, and substantial economic burden. They account for one-third of referrals to gastroenterology clinics.⁴ FGIDs significantly impact the quality of life (QoL) and healthcare costs. Patients with FGIDs struggle with higher average annual prescription and indirect costs. Employees with FGIDs incur higher healthcare costs, have more days of absence, and demonstrate lower workplace productivity.⁵

Given the multiple pathophysiological mechanisms of FGIDs, various pharmacological medications or combinations may be required for treatment. Symptom-based treatment may be effective for diarrhea-dominant or constipation-dominant disorders. In addition, antidepressants can be particularly beneficial because of their effects on the gut and brain.⁶

5HT-agonists/antagonists, locally mediated drugs, and centrally acting drugs are considered for their stress-related effects on the gut.³ Sulpiride, a dopamine agonist, is primarily used at high doses as an antipsychotic for the management of schizophrenia. Additionally, it increases gastric motility and slows gastric emptying, making it a useful adjunctive treatment option for duodenal ulcers.⁷ According to the British Society of Gastroenterology guidelines, sulpiride can be used as a second-line agent for the treatment of FD.⁸

Mebeverine is an antispasmodic medication that relieves abdominal pain caused by spasms and functional disorders in the intestinal smooth muscles, particularly in IBS. It helps regulate bowel movements and relaxes the intestinal smooth muscles.⁹ At doses between 135 and 270 mg, mebeverine demonstrates low anticholinergic side effects. Mebeverine was recognized as a treatment option for IBS in the 1960s. Chakraborty et al. reported a considerable reduction in IBS symptoms with immediate-release and controlled-release formulations of mebeverine.¹⁰

This study aimed to evaluate the safety and efficacy of a combination of 100 mg mebeverine and 25 mg sulpiride (Colona®) in patients with FGIDs.

Methods

Design

This was a Phase IV, multicenter, prospective, open-label, cohort study conducted in Egypt to evaluate the safety and efficacy of the combination of mebeverine and sulpiride in patients with FGIDs. Written informed consent was obtained prior to study-related procedures.

Each patient was assessed against the selection criteria. The total participation duration was approximately 3 weeks, consisting of a 1-week screening period and a 2-week (±1 week) treatment period. The treatment duration included two visits: a baseline visit and a follow-up visit after 2 weeks (±1 week). All patient details were deidentified.

Setting

The study was conducted at three active sites in Egypt: The National Hepatology and Tropical Medicine Research Institute (NHTMRI), New Cairo Hospital, and the Department of Tropical Medicine and Infectious Diseases at Tanta University Hospital. The study was approved by the research ethical committee of Tanta Faculty of Medicine (Approval Number: 30430/07/15). The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.¹¹

Study population

The study included 253 patients fulfilling the following criteria: (a) males and females aged 18 to 60 years diagnosed with FGIDs, including FD, IBS, functional gastrointestinal colic, and postdysenteric colitis; (b) patients with GI manifestations accompanied with psychogenic and migraine-like headaches; (c) patients willing and able to complete all study visits and procedures; and (d) patients capable of providing written informed consent in a consecutive order.

Patients with the following criteria were excluded: (a) patients with alarming symptoms suggestive of organic GI disorders (e.g. bleeding per rectum, melena, and marked weight loss); (b) patients with a history of inflammatory bowel disease; lactose intolerance; malignancy; major hepatic, renal, or hematological diseases; and those who underwent laparoscopic or open abdominal surgery within the previous 6 months; (c) patients with a history of peptic ulcer disease, GI bleeding, intestinal stenosis or obstruction, and pancreatic insufficiency within the previous 6 months; (d) patients with a history of a known allergy to the study drug and patients taking concomitant medications that act on or influence GI tract motility (e.g. cholagogues and prokinetic agents); (e) patients who were maintained on antidepressant or anxiolytic treatment; and (f) pregnant or lactating female patients and female patients of childbearing age not using contraception.

Intervention

The study drug consisted of film-coated tablets containing 25 mg sulpiride and 100 mg mebeverine HCL. One tablet was administered 3–4 times daily (preferably 20 min before meals). The treatment duration was 2 weeks.

Outcome measures

Outcome measures were assessed at baseline and after 2 weeks (±1 week). Tailored gastrointestinal symptoms rating scale (tGSRS) was used to evaluate the efficacy of mebeverine and sulpiride in patients with FGIDs.¹² The gastrointestinal symptom rating scale (GSRS), foundation for tGSRS, is recognized as a valid and reliable tool for evaluating GI symptoms. Numerous studies have demonstrated its internal consistency (Cronbach’s alpha generally between 0.61 and 0.87 across domains) and test-retest reliability (intraclass correlation coefficient (ICC) ranging from 0.36 to 0.75 in different translations and contexts).^13–15

Currently, there are no documented studies on the local validation of the GSRS or tGSRS specifically in an Egyptian population. However, the GSRS has been used in Egyptian research in some previous studies.¹⁶

Primary efficacy outcome measures were as follows: (a) relative percent change in the total tGSRS score and (b) number of patients achieving ≥50% relative improvement in the total tGSRS score.

Primary safety outcome measures included the occurrence of study drug-related adverse events (AEs)/serious adverse events (SAEs), represented as incidence and attack rates.

Secondary outcome measures were as follows: (a) number of patients achieving improvement of “at least one point scale reduction” in the tGSRS for each presented symptom; (b) number of patients with relief or improvement based on the overall physician assessment of clinical outcome; (c) time to relief/improvement to the presented symptoms as per physician assessment of the clinical outcome; (d) mebeverine and sulpiride overall tolerability, as assessed by physician/patient; (e) number of patients compliant with the prescribed medication and reasons for noncompliance, if any; and (f) number of patients who discontinued the study drug due to AEs.

At the baseline visit, the investigators conducted a physical examination and assessed vital signs. They completed the baseline tGSRS questionnaire to rate the intensity, frequency, duration, request for relief, and impact on social performance of the presented GI tract symptoms. The investigators prescribed mebeverine and sulpiride at their sole discretion, guided by the summary of product characteristics (SmPC). Patients were provided a laboratory referral form to undergo the specified tests 2–3 days before their next visit. Any AEs or SAEs occurring from the informed consent date were recorded along with any concomitant medications.

At the end of the study visit, the investigators assessed the laboratory results and completed the follow-up tGSRS questionnaire to evaluate changes in the intensity, frequency, duration, request for relief, and impact on social performance of the presented GI tract symptoms. A thorough medical evaluation, including physical examination and vital signs assessment were carried out. The occurrence of AEs and SAEs since the previous visit and any changes in concomitant medications were recorded. Assessment of the overall clinical outcome by the physician and assessment of the physician/patient’s overall tolerability of mebeverine and sulpiride by the physician and patient were documented.

Statistical analysis

Wilcoxon signed-rank test was used to compare the mean scores at baseline and at the end of the study. Paired t-test and repeated measure analysis of variance (ANOVA) test was used to estimate the change in numerical variables throughout the study visits (depending on the distribution of data, nonparametric substitution tests were applied). Chi-square test was used for unpaired categorical variables and McNemar’s test for paired categorical variables.

Ethical considerations

The patient written informed consent form adhered to all local regulations, International Conference on Harmonization Good Clinical Practice (ICH-GCP) standards, and ethical principles. The study was conducted in full accordance with the Declaration of Helsinki, as revised in 2024.

Results

Data collection

A total of 292 patients were screened, of which 253 met the eligibility criteria and were enrolled in the study, whereas 39 (13.36%) patients did not meet the criteria and were excluded. The eligible study population had a mean (±SD) age of 41.79 ±10.94 years. The demographic characteristics of the patients at baseline are presented in Table 1. The screening period lasted 1 week, during which no treatment was prescribed. Medical history and current medications were recorded, and physical examination and vital signs were assessed. Patients were tested for the following: urea, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Patients were also instructed to discontinue any medications prohibited by the study protocol. To exclude patients with organic GI disorders, abdominal ultrasound and stool analysis were performed for all patients.

Table 1.

Demographic data at baseline.

Demographic characteristics	Valuesn (%)
Sex
Male	61 (24.1%)
Female	192 (75.9%)
Marital status
Married	232 (91.7%)
Single	14 (5.5%)
Divorced	4 (1.6%)
Widowed	3 (1.2%)
Education level
Uneducated	69 (27.3%)
Basic education	66 (26.1%)
Secondary school graduate	73 (28.9%)
College graduates	43 (17%)
Masters/PhD holders	2 (0.8%)
Employment
Unemployed	174 (68.8%)
Employed	79 (31.2%)
Residence
Urban areas	130 (51.4%)
Rural areas	123 (48.6%)

The baseline physical examination results of 194 (76.7%) patients were normal, whereas 59 (23.3%) patients demonstrated abnormal but nonclinically significant findings. Abdominal ultrasound findings were normal for 107 (42.3%) patients, whereas 146 (57.7%) patients exhibited abnormal findings not suggestive of organic GI disorders. Stool analysis results were normal for 140 (55.3%) patients, whereas 113 (44.7%) patients exhibited abnormal findings not indicative of organic GI disorders. The mean (±SD) systolic blood pressure was 118.75 ± 9.74 mmHg, mean (±SD) diastolic blood pressure was 78.25 ± 7.87 mmHg, mean (±SD) heart rate was 77.45 ± 6.13 beats/min, and mean body temperature was 36.99 ± 0.17°C.

Among the eligible patients, 52 (20.6%) had a history of at least one concomitant disease. Hypertension was the most frequently reported condition, affecting 26 (10.28%) patients, followed by diabetes mellitus in 23 (9.09%). Asthma, hepatitis C, and hypotension were reported in 2 (0.79%) patients.

Among the eligible population, 70 (27.67%) were taking concomitant medications during the study. The most frequently used medications were bisoprolol and glimepiride, taken by 9 (3.56%) patients, followed by pantoprazole by 7 (2.77%) patients, insulin by 6 (2.37%) patients, captopril by 5 (1.98%) patients, and amlodipine and paracetamol by 3 (1.19%) patients.

Efficacy

Regarding the primary efficacy results, the baseline tGSRS mean (±SD) score was 11.42 ± 4.10. After 2 weeks (±1 week) of treatment with mebeverine and sulpiride, the tGSRS significantly (p < 0.0001) decreased to 3.11 ± 2.48, corresponding to a mean (±SD) relative improvement of 71.84% ± 20.56%.

Among the 253 patients, 227 patients (89.72%, 95% confidence interval (CI): 85.96%–93.49%) demonstrated a ≥50% relative improvement in the total tGSRS score, whereas 26 (10.28%) patients did not demonstrate this improvement.

The number of patients who achieved an improvement of “at least one point scale reduction” in the tGSRS for each presented symptom is demonstrated in Table 2.

Table 2.

Number of patients achieving improvement “at least one point scale reduction” in tGSRS for each presented symptom.

Symptom	Patients achieving improvementN = 253, n (%)
Abdominal distension	221 (87.35%)
Epigastric/abdominal pain	200 (79.05%)
Early satiety/ postprandial fullness	192 (75.89%)
Nausea and vomiting	189 (74.70%)
Feeling of incomplete evacuation	150 (59.29%)
Hard stools	147 (58.10%)
Urgent need for defecation	137 (54.15%)
Loose stools	128 (50.59%)
Increased passage of stools	126 (49.80%)
Decreased passage of stools	119 (47.03%)

tGSRS: tailored gastrointestinal symptoms rating scale.

According to the physician’s overall assessment of the clinical outcomes, 238 (94.1%) patients reported relief or improvement in the symptoms; of which, 59 (23.3%) patients demonstrated total improvement, 179 (70.8%) showed partial improvement, 14 (5.5%) reported no change, and 1 (0.4%) exhibited worsening of symptoms.

The median time to clinical success (relief/improvement) of the presented symptoms was 14 days (95% CI: 13.66–14.34 days).

Based on the physician’s judgment, the overall tolerability of mebeverine and sulpiride was excellent in 226 (89.3%) patients, fair in 26 (10.3%) patients, and poor in 1 (0.4%) patient. However, according to the patient’s assessment, the tolerability was excellent in 137 (54.2%) patients, fair in 110 (43.5%) patients, and poor in 6 (2.4%) patients.

In terms of compliance, 252 (99.6%) patients were compliant, whereas 1 (0.4%) patient was noncompliant due to treatment negligence.

The efficacy results demonstrated a significant improvement (p < 0.0001) in FGID symptoms after 2 weeks of treatment, with a mean tGSRS score showing a 71.84% ± 20.56% relative improvement. Furthermore, 89.72% (95% CI: 85.96%–93.49%) of patients achieved ≥50% relative improvement in their scores.

According to the overall physician assessment of the clinical outcomes, 94.1% of patients experienced relief or improvement of their symptoms after a median time of 14 days (95% CI: 13.66–14.34 days).

Safety

During the study, 4 AEs (attack rate, 0.015) were reported in 4 (1.58%) patients, whereas 249 (98.42%) patients did not experience any AEs. Two (0.79%) patients experienced diarrhea (one event was mild and the other was moderate in severity), 1 (0.4%) patient experienced mild dyspepsia, and 1 (0.4%) patient experienced moderate galactorrhea.

All reported events were nonserious and exhibited good recovery. No corrective treatment was administered for any of the 4 events.

For cases of mild diarrhea and dyspepsia, no action was taken regarding the study medication; however, the medication was withdrawn (temporarily, permanently, or delayed) in cases of moderate diarrhea and galactorrhea.

Regarding the relationship of the AE to the study medication, mild diarrhea and dyspepsia were considered possibly related, whereas moderate diarrhea was considered probably/likely related, and galactorrhea was considered related to the study medication. Further details are described in Table 3.

Table 3.

Detailed description of adverse events.

System organ class (SOC)	Preferred term (PT)	Severity	Corrective treatment	Seriousness criteria	Outcome	Action taken with study drug	Relationship to study drug
Reproductive system and breast disorders	Galactorrhea	Moderate	No	No	Recovered	Withdrawn (temporarily, permanently, or delayed)	Related
Gastrointestinal disorders	Dyspepsia	Mild	No	No	Recovered	None	Possibly related
Gastrointestinal disorders	Diarrhea	Moderate	No	No	Recovered	Withdrawn (temporarily, permanently, or delayed)	Probable/ likely related
Gastrointestinal disorders	Diarrhea	Mild	No	No	Recovered	None	Possibly related

Data of adverse events were coded using MedDRA (Medical Dictionary for Regulatory Activities) version 19.

All patients completed the study as per protocol except for one patient who discontinued the treatment after the baseline visit due to an AE.

No significant differences were observed between the baseline visit and follow-up in the patient’s body weight, systolic and diastolic blood pressure, heart rate, body temperature, serum urea and creatinine levels, and glutamic pyruvic transaminase (SGPT) and glutamic oxaloacetic transaminase (SGOT) levels, except for serum creatinine level, which increased from 0.71 ± 0.18 mg/dL at baseline to 0.72 ± 0.15 mg/dL at follow-up and showed a statistically significant difference (p = 0.049); however, this difference was not clinically significant.

Discussion

This cohort study evaluated the safety and efficacy of mebeverine and sulpiride in patients with FGIDs. The GSRS is an effective disease-specific tool used to assess GI symptoms according to symptom review and clinical experience. It consists of 15 points rated on a seven-point scale ranging from no discomfort to severe discomfort. The patient’s score can be calculated using the mean of the total points, where higher scores indicate greater symptom severity.¹³

According to the efficacy results of mebeverine and sulpiride, the mean tGSRS score significantly decreased from baseline after 2 weeks of treatment, indicating relative improvement in the experienced symptoms. Most patients reached ≥50% relative improvement in the tGSRS score, further establishing the efficacy of the study drug. A study conducted on the effect of mebeverine in improving IBS symptoms using the IBS QoL questionnaires also demonstrated a decrease in the mean score after 4 weeks and more than 50% decrease in symptom severity after 8 weeks of treatment.¹⁷

In terms of patient improvement in tGSRS with “at least one point scale reduction,” most patients demonstrated improvement in abdominal distension and epigastric/abdominal pain. These findings may be correlated to the fact that abdominal pain is considered highly prevalent in the primary care population.¹⁸ Improvement was also noticed in early satiety/postprandial fullness, nausea and vomiting, feeling of incomplete evacuation, hard stools, urgent need for defecation, loose stools, and increased and decreased passage of stools. A study comparing the efficacy of mebeverine versus pinaverlum bromide for patients with IBS demonstrated improvement in the daily defecation frequency and stool consistency with mebeverine after 2 weeks of treatment.¹⁹

Based on the physician’s judgment, the median time for clinical improvement was 2 weeks, which was relatively shorter than that of another study assessing the efficacy of sulpiride for FD, where an improvement in nausea and belching and complete disappearance of vomiting and pain were observed after 4 weeks of treatment.⁷

According to the physician’s assessment, most patients experienced relief or improvement of symptoms after the study duration, with few patients reporting no change and one demonstrating worsening of symptoms. These results were consistent with those of a crossover study comparing the efficacy of sustained-release and immediate-release mebeverine in patients with IBS. In the study, among 60 patients, 44 (73%) experienced improvement in symptoms after 3 weeks of treatment, whereas one (1.67%) patient reported worsening of symptoms with the immediate-release formulation. At 6 weeks, 13 (21.6%) patients demonstrated improvement in symptoms.²⁰

Based on the physician’s assessment, most patients demonstrated excellent tolerability; 26 tolerated the treatment fairly, and only one exhibited poor tolerance. In contrast, according to patient’s assessment, fewer patients reported excellent tolerance, with 110 patients reporting fair tolerance and six patients reporting poor tolerance to mebeverine and sulpiride. These findings highlight a discrepancy between physician and the patient judgments, which is consistent with that of a study examining the perception of physicians and patients with FGIDs through telephone call requests. In the study, patients described their symptoms and procedure-related concerns. The results indicated that patients tended to believe their symptoms to be more disabling and severe, whereas physicians were more inclined to minimize the severity of these described symptoms.²¹

Most patients were compliant with the prescribed treatment, with only one noncompliant due to treatment negligence. These results align with those of a randomized control study on the management of IBS using mebeverine, methylcellulose, placebo, and a cognitive behavioral therapy (CBT) self-management program, which reported 80% compliance to the prescribed medication. Noncompliance was attributed to either worsening of symptoms or unspecified reasons.²²

Four AEs experienced by four patients were documented during the study. Among these patients, one experienced diarrhea, one patient had mild dyspepsia, and one had moderate galactorrhea. According to the World Health Organization (WHO) causality assessment, mild diarrhea and dyspepsia were considered possibly related to the study medication, moderate diarrhea was considered probably related, and galactorrhea was considered related to the study medication. In a study evaluating the safety of immediate-release versus sustained-release mebeverine, two patients discontinued the study due to AEs, one patient experienced epigastric discomfort, and one patient reported nausea; however, it was uncertain whether these events were drug-related AEs.²³

Overall, the study results on mebeverine and sulpiride demonstrated significant improvement in the symptoms of FGIDs. Most patients achieved ≥50% relative improvement in their rating scores and, according to the assessment, most patients experienced symptomatic relief after 14 days of treatment. Most patients did not report any AEs during the study period, and all reported AEs were nonserious. These results support the use of mebeverine and sulpiride for the treatment of FGIDs.

Our study has several limitations. First, it was a single-arm trial without randomization or a control group such as placebo or standard treatment, which limits the ability to definitively prove efficacy, although it demonstrates promising outcomes and safety. Second, the open-label design may have introduced expectation bias from patients and doctors. Third, as the GSRS is patient-reported, it is particularly susceptible to bias. Fourth, baseline characteristics were not balanced through stratification; a higher proportion of patients were female, from rural areas, uneducated, or unemployed, factors that may influence severe FGIDs or placebo responses. Fifth, the short follow-up period restricted evaluation of long-term effects and side effects, such as drug dependence or tolerance. Finally, the study did not analyze outcomes across different FGID subgroups; therefore, future research should focus on identifying the subgroups that respond better to treatment.

Conclusion

This study demonstrated that a combination of mebeverine and sulpiride (Colona®) may be an effective treatment option for FGIDs. The findings revealed notable symptom improvements, potentially enhancing patients’ QoL. The combination therapy was generally well tolerated, with a safety profile comparable to that of existing treatments. Although further research is warranted to verify long-term safety and effectiveness across different patient groups, these preliminary results suggest that mebeverine and sulpiride could represent a viable option for managing FGIDs and an alternative treatment strategy for patients with limited treatment choices.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251410412 - Supplemental material for Evaluation of safety and efficacy of the combination of mebeverine and sulpiride in treatment of patients with functional gastrointestinal disorders: A prospective cohort

Supplemental material, sj-pdf-1-imr-10.1177_03000605251410412 for Evaluation of safety and efficacy of the combination of mebeverine and sulpiride in treatment of patients with functional gastrointestinal disorders: A prospective cohort by Mohamed El-Kassas, Ahmed Tawheed, Hesham El Halwagy, Reem Ezzat, Amr El Fouly and Asem Elfert in Journal of International Medical Research

Footnotes

Acknowledgments

We acknowledge the use of the Grammarly tool solely for punctuation editing; all scientific content and intellectual insights remain the sole responsibility of the authors.

Author contribution

Mohamed El-Kassas: Conceptualization. Ahmed Tawheed: Writing – Review & Editing. Hesham El Halwagy: Investigation, Formal analysis. Reem Ezzat: Investigation. Amr El Fouly: Writing – Original Draft. Asem Elfert: Supervision.

Data availability statement

All data can be provided upon reasonable request.

Declaration of conflicting interests

The authors declare no competing interests for this work.

Funding

This was a funded study by Rameda Pharmaceutical Company. The funders had no role in study design, data collection, data analysis, or data interpretation.

ORCID iD

Ahmed Tawheed

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