|Year : 2023 | Volume
| Issue : 1 | Page : 6-13
Efficacy and safety analysis of prucalopride in refractory chronic constipation cases in a tertiary care hospital in Eastern India: A randomized, single-blind, placebo-controlled study
Suhasini Dehury1, Sourya Mohapatra2, Haribhakti Seba Das3, Siddhartha Goutam4, Chetna Kaushik4
1 Department of Pharmacology, Materiovigillance Program, SCB Medical College and Hospital, Cuttack, Odisha, India
2 Department of Pharmacology, S. C. B. Medical College and Hospital, Cuttack, Odisha, India
3 Department of Gastroenterology, S. C. B. Medical College and Hospital, Cuttack, Odisha, India
4 Department of Pharmacology, S. C. B. Medical College, Cuttack, Odisha, India
|Date of Submission||28-Jul-2022|
|Date of Decision||08-Feb-2023|
|Date of Acceptance||09-Feb-2023|
|Date of Web Publication||20-Mar-2023|
Department of Pharmacology, S. C. B. Medical College, Cuttack, Odisha
Source of Support: None, Conflict of Interest: None
OBJECTIVES: Chronic constipation (CC), a common functional gastrointestinal disorder, has laxatives as its mainstay of treatment. Refractoriness to laxatives calls for better treatment options. Prucalopride is a novel, well-tolerated enterokinetic with high 5-hydroxytryptamine 4 receptor selectivity. This study was undertaken with the intention to establish the efficacy and safety of prucalopride with placebo in adults with refractory CC.
MATERIALS AND METHODS: Patients were screened and 180 patients fulfilling the inclusion criteria were simply randomized into 2 groups either to receive prucalopride 2 mg (n = 90) or placebo (n = 90) once daily for a duration of 12 weeks. The efficacy endpoints (primary) were intended to measure the proportion of patients with three or more spontaneous complete bowel movements (SCBMs) per week over 12 weeks. Secondary endpoints were assessed via the validated questionnaires. Adverse events, electrocardiogram, and other laboratory parameters were monitored at different time intervals.
RESULTS: Efficacy and safety were analyzed in 180 patients simply randomized (1:1) into group A (prucalopride arm, n = 90) and group B (placebo arm, n = 90). Patients having three or more SCBMs per week in the prucalopride arm (2 mg) were 41% as against to 12% in the placebo arm (P < 0.001). A significant increase (P < 0.001) in the number of spontaneous bowel movements per week plus an increase of average bowel movement by 1 point per week was seen in the prucalopride arm. Secondary efficacy endpoints which included patients' treatment satisfaction, improvement in the perception of constipation symptoms using the patient assessment of constipation -symptoms and stool consistency score changes were more pronounced in the prucalopride arm than the placebo. The most common adverse events reported from both the groups were headache, nausea, bloating, and diarrhea. No significant cardiovascular changes or laboratory abnormality was detected throughout the study period.
CONCLUSION: Prucalopride is effective in laxative refractory CC cases with a good safety profile.
Keywords: Chronic constipation, enterokinetic, laxative refractory, prucalopride
|How to cite this article:|
Dehury S, Mohapatra S, Das HS, Goutam S, Kaushik C. Efficacy and safety analysis of prucalopride in refractory chronic constipation cases in a tertiary care hospital in Eastern India: A randomized, single-blind, placebo-controlled study. Indian J Pharmacol 2023;55:6-13
|How to cite this URL:|
Dehury S, Mohapatra S, Das HS, Goutam S, Kaushik C. Efficacy and safety analysis of prucalopride in refractory chronic constipation cases in a tertiary care hospital in Eastern India: A randomized, single-blind, placebo-controlled study. Indian J Pharmacol [serial online] 2023 [cited 2023 May 28];55:6-13. Available from: https://www.ijp-online.com/text.asp?2023/55/1/6/372162
| » Introduction|| |
Chronic constipation (CC) in adults is a well-documented functional gastrointestinal (GI) disorder with a worldwide prevalence of around 20% (approximately)., It is currently being defined as a multisymptom complex disorder according to the ROME IV criterion. Several studies indicate its occurrence to be greater in non-Caucasians, the elderly age group, women, and hospitalized elderly persons. Though scarce, still Indian data estimate that around 16.8% (ROME II) of the adult population is chronically constipated.
To date, management of CC has focused mostly on nonpharmacological measures, i.e., lifestyle modification, increased dietary fiber, and fluid intake. Apart from that in medical management, laxatives have been playing a predominant role for ages. However, in the long run, majority of the patients have been found to develop either laxative resistance or refractoriness.,,
Practically, it is a cumbersome job on part of a treating physician to label a CC patient as treatment-resistant or refractory based only on complaints alone as, other contributing factors may have a role to play. “A CC patient can be labeled to be a case of true refractory constipation if after all careful diagnostic and therapeutic evaluations he/she fulfills standard diagnostic criteria for functional constipation, lacks any alarming feature for organic conditions, and fails to improve upon intake of a high-fiber diet and laxatives either a stimulant or osmotic ones.”
Although a cocktail of pharmaceutical products are available in the market for the management of CC in adults, pharmacotherapy of refractory constipation still poses a great challenge for physicians. With widening patient dissatisfaction and increasing refractoriness with the available options, a lookout for new, safe, and effective treatment is much needed.
One such novel group of drugs discovered is prokinetics (5-hydroxytryptamine [5-HT]-4 agonists), which acts by increasing intestinal motility and thus giving relief from constipation symptoms. Cisapride and Tegaserod, previously used for chronic constipation, are now withdrawn from the market for their dangerous CVS side effect profile.,
Recently, another newer, potent enterokinetic, having high 5-HT4 receptor agonistic activity and lower human ether-a-go-go-related gene channel affinity, prucalopride, was approved by the Food and Drug Administration in 2018,, and was being widely used by the European Union since 2010.,, This drug acts mainly via enhancement of colonic motility through maximum action on 5-HT-4 receptors, leading to relief from constipation. In several phases of placebo-controlled clinical trials, prucalopride has shown remarkable results by improving the frequency, and consistency of bowel movements, and satisfaction among the participants.,, It was found to be safe and well-tolerated, with the least effect on the cardiovascular system in therapeutic doses for adults with CC than its previous counterparts, i.e., cisapride and tegaserod.
Many studies have been done in India providing evidence for various drugs in the treatment of CC. However, data with recently approved prucalopride in refractory CC cases are lacking in our setup. Hence, given the known evidence of prucalopride's effectiveness in different CC scenarios, this study was undertaken with an aim to access the efficacy and safety profile of prucalopride with placebo over a 12 weeks' time frame in adults with refractory CC.
| » Materials and Methods|| |
This was a prospective, randomized, single-blind, placebo-controlled, parallel-group study conducted in the Department of Gastroenterology in collaboration with the Department of Pharmacology, S. C. B MCH, Cuttack, Odisha, for a duration of 12 months (January 2019 to January 2020). Prior ethical approval from the IEC/IRB S. C. B MCH, Cuttack (Ethics ID no. 864/14.10.19, ref no. 13351), and written informed consent from the study subjects were taken before the beginning of the study.
Adult patients (≥18 years) of either sex who presented to the outpatient department (OPD) gastroenterology with a history of CC fulfilling the Rome IV criterion and with a history of nonresponsiveness to laxative treatment for the last 6 months were included in the study. All the included patients were provided with all necessary details related to the study along with the procedures and follow-up schedules in properly documented sheets.
Patients were examined and excluded if cause of CC was secondary in nature, i.e., medications, any metabolic, endocrine, or neurologic disorders, surgery, or anatomical intestinal issues. Patients having any cardiovascular, liver, renal, or psychiatric disorder or any known adverse drug reaction (ADR) to study drug and excipients were excluded. Pregnant and breastfeeding women were also excluded from our study.
Out of 560 patients screened, 180 patients (intention-to-treat population) who fulfilled the inclusion criteria were simply randomized (1:1) and allocated to 2 groups using a random number table by the treating physician. Group A (n = 90) patients were to receive tablet prucalopride 2 mg and Group B (n = 90) patients were to receive placebo (similar-looking tab) once daily just before breakfast for a period of 12 weeks. Follow-up was eventually done at 4, 8, and 12 weeks.
After the 1st visit, data about demographic details, clinical, medical, and constipation history (details of onset, duration, stool form, consistency, and frequency) and electrocardiogram (ECG) details along with proper physical examination findings of all participants were recorded in proper case record form. Laxative intake if any was stopped prior to study entry and all participants were asked to keep a note of their number of average spontaneous complete bowel movements (SCBMs)and spontaneous bowel movements (SBMs)per week. till 12weeks. They were also asked to note the frequency, consistency of stool along with any adverse reaction occurring during the study period till end of 12weeks. Subjects were directed not to undertake any nonpharmacological treatment affecting bowel function (colon irrigation and acupuncture) or change their current diet, or lifestyle till completion of the study period.
Rescue and disallowed medications
Tablet bisacodyl (10 mg) (Dulcoflex, Boehringer Ingelheim) twice daily was kept as a rescue medication for those patients who did not have a bowel movement for ≥72 h during the 12 weeks of study duration and enema for those who were unresponsive to rescue medication. The number of rescue medications used during the study period per patient was documented. Rescue medication and enema were not allowed 48 h before and during randomization.
Primary outcome assessments
After the patients were enrolled, the percentage of patients having on an average 3 or more than 3 SCBMs /week(SCBMs: bowel movement with a sense of complete evacuation), no. of SCBMs/week, and no. of SBMs/week during the 12 weeks of study period was considered to be our primary efficacy endpoint.The secondary efficacy endpoints included the assessment of improvement in CC symptoms in patients using the “validated 12-item Patient Assessment of Chronic Constipation Symptoms (PAC-SYM) questionnaire” and its subsymptom score which included abdominal, rectal, and stool symptoms. The overall PAC-SYM score was anywhere between 0 = absent to 4 = very severe. One-point increase in overall score from baseline was necessary for clinical significance. Assessment of stool form was done using the Bristol Stool Form Scale through 4, 8, and 12 weeks. Overall treatment satisfaction assessment was done using the 5-point Likert scale at baseline and end of 12 weeks. ECG for all participants was done at 0 and 12 weeks.
Telephonic communication was done to obtain data from patients who were unable to attend the OPD on given dates.
Data of all participants who took prucalopride even once was recorded. Vital signs along with ECG findings were recorded at baseline and end of 12 weeks. Any ADR reported during the study duration was noted in the suspected ADR Reporting form of Indian Pharmacopoeia Commission -National Coordinating Center (IPC-NCC). Causality assessment and severity assessment was done using WHO-UMC Scale and Hartwig's severity scale, respectively.
Participants who reported at least once in the follow-up visit postbaseline were included for analysis. Safety analysis was done for all randomized patients. Statistical Package for the Social Sciences software (SPSS version 20.0, IBM SPSS inc., Chicago, IL, USA) was used for data analysis. Descriptive data were presented as percentages and mean ± standard deviation. Chi-square test of significance was used for categorical data. Student's t-test was used to compare the difference in means between the groups. P <0.05 was considered statistically significant.
| » Results|| |
Patient characteristics and baseline demographics
This was a hospital-based, prospective, single-blind, randomized controlled study. Patients with a history of CC not responding to laxative treatment presenting to the OPD of the Department of Gastroenterology, SCB Medical College and Hospital, Cuttack, between January 2019 and January 2020 were screened and included as shown in [Figure 1].
The baseline demographic parameters of all study participants are noted in [Table 1]. Maximum patients were male (59%) with a mean age of 59.8 years with a range between 30 and 70 years. Maximum patients were above 60 years (52%). There was no difference in patient's weight, height, and body mass index distribution in both the groups. Patients in both the groups had a history of an average duration of constipation of 6.7 years. Peptic ulcer disease and anxiety were the most common comorbidities associated with CC in both the groups.
Prior to the study entry, there was no difference in the mean SCBM per week in the prucalopride arm (0.7) and placebo arm (0.6) [Figure 1]. At baseline, 37% in the test group and 33% in the placebo group had no SBM per week, and 25% on average in both the groups had SBMs between 1 and 3, and overall, 13% had ≥3 SBMs/week. There was also no statistical difference in the mean SBM per week at baseline in both the arms [Figure 2]. Eighty-five percent of patients expressed dissatisfaction with their previous treatment with laxatives prior to study entry.
|Figure 2: Mean spontaneous complete bowel movements per week (SCBMs/week) in Study Subjects (n = 180). SCBM = Spontaneous complete bowel movement|
Click here to view
Efficacy parameters assessment
Primary endpoint assessment
Patients reporting ≥3SCBMs/week (%) averaged over 12 weeks were as follows:
During the baseline visit, 10 (11) patients in the prucalopride arm and 6 (6) patients in the placebo arm reported an average of ≥3 SCBMs/week and an overall of 25 (14) patients from both arms reported ≥3 SBMs/week. The number of bowel movements was similar in both the groups at the 0 weeks.
By the end of 12 weeks of treatment, a statistically significant number of patients had a higher number of three or more than three SCBMs in the prucalopride group (31%) than in the placebo (15%; P ≤ 0.005) [Table 2]. The mean number of SCBMs over 4–12 weeks also improved in the prucalopride arm than the placebo (P < 0.001 for all cases) at the end of 12 weeks [Figure 2]. The mean number of SBMs through 4–12 weeks also increased significantly in the prucalopride arm from 0.8 to 3 in contrast to 0.6–1.7 in the placebo arm. Patients achieving at least ≥1 SCBMs/week over 4–12 weeks were also significantly higher (P < 0.005) in test arm than placebo. Patients in the prucalopride arm reported 1st SCBM after 2 days of treatment initiation, while patients in the placebo arm reported the same after 5 days.
Secondary efficacy endpoints assessment
Prior to the start of the study, patients of both the arms reported an average of 0.6–1 SCBM/week. When followed through 4, 8, and 12 weeks of treatment, patients in the prucalopride arm reported a significant (P ≤ 0.001) increase of ≥1 SCBM/week from baseline as compared to the placebo arm [Table 2] and [Figure 2]. When followed through 4–12 weeks, the mean number of SCBMs per week was also high in the prucalopride arm than the placebo [Figure 2]. Through weeks 4–8, the response rate was 42% in the prucalopride arm and 17% in the placebo arm (P ≤ 0.001, in both the cases) [Table 2].
Other secondary endpoints as compared to the placebo also improved significantly in the prucalopride arm over 12 weeks of treatment. Data comparing the results through the weeks (4, 8, and 12 weeks) showed that prucalopride had significantly improved: the percentage of patients reporting an increase of SBM/week, (P ≤ 0.001 in all cases), mean SBMs/week., the number of SCBMs/week (P ≤ 0.001 in all cases), the number of bowel movements having normal consistency, and form as assessed via the Bristol Stool Scale scores (P ≤ 0.05 in all cases).
At baseline and week 4, there was no difference in the use of number of rescue medication (bisacodyl tablets) but through 8–12 weeks patients in the prucalopride arm used less number of rescue medication (bisacodyl tablets) as compared to that of placebo (P ≤ 0.05 for all cases) [Table 2]. Fifty-two percent in the test arm and 36.5% in the placebo arm did not use the rescue medication.
At baseline, 77 (85%) in Group A had hard to very hard stool consistency (Bristol Stool Scale type 1, 2, and 3) and only 14% had normal to soft type stool consistency (type 4 and 5) and none had diarrhea (type 6 and 7). while 63(70%) subjects in group prucalopride had type 1, 2, 3 Bristol Stool Scale scores(BSS) and 11% had normal to soft type 4,5 BSS scores with no cases of diarrhea at presentation. There was no significant difference at baseline. At end of 12 weeks, there was a significant improvement in the stool consistency in the prucalopride arm compared to the placebo arm. Fifty-one percent (67 patients) treated with prucalopride had normal to soft stool consistency (Types 4 and 5) in contrast to only 27% in the placebo arm (P ≤ 0.05). A total of 10 (11%) patients in the prucalopride arm and 3 (3%) patients in the placebo arm reported diarrhea (Types 6 and 7).
Patient chronic constipation symptom assessment via PAC-SYM questionnaire
Compared to placebo, significant improvement (P ≤ 0.05, in all cases) in the overall, stool, abdominal, and stool symptom PAC-SYM score was more pronounced in patients of the prucalopride arm from baseline [Table 2].
Patient therapeutic satisfaction assessment: 5-point Likert scale
At baseline, 53 (59%) in the prucalopride arm and 47 (52%) in the placebo arm were highly dissatisfied with their previous treatment. After 12 weeks of treatment, 68 (75%) patients in the test arm were high to somewhat satisfied with their treatment in contrast to only 23 (25%) in the placebo arm [Table 2], which indicated a statistically significant improvement (P ≤ 0.001) in therapeutic satisfaction level in the prucalopride arm.
Safety and tolerability
Participants from both the arms reported treatment-related adverse events. Nausea, diarrhea, and headache were most commonly reported from the prucalopride arm, while bloating and flatulence were common in the placebo arm [Figure 3]. The majority of the ADRs reported were within the pharmacological profile of the study drug. ADRs were mild to moderate in severity as assessed by the modified Hartwig and Seigel scale. No new safety signals were detected. No death or hospitalization was recorded during the study period. Both the arms noted no clinically relevant cardiovascular findings, ECG changes, or abnormal laboratory parameters during the study period.
| » Discussion|| |
CC is a multisymptom complex disorder with a major impact on the physical, social, and mental well-being (i.e., quality of life) of the subjects. It affects persons of all ages and sex with a very negative effect on the quality of life of patients in long run. With increasing refractoriness to traditional laxatives, treatment of the same has become cumbersome. Our study drug prucalopride, a new generation enterokinetic, was found to be effective in relieving symptoms by improving impaired colonic motility with a lesser side effect profile. However, its role in disease reversal or total eradication of constipation pathology yet remains to be proved in future trials.
This study in the Indian population comprising adults with refractory CC had a male predominance of 59%, which was in line with the study conducted by Ray and Shah et al., However, our findings were in contradiction to several western studies, where female preponderance was seen.,, Our study had 68% of patients in the ≤65 years age group, which was similar to a study done by Kanaki et al.
Peptic ulcer disease and anxiety were the most commonly found comorbidities associated with CC in our study, which was similar to studies done by Choung et al. and Shah et al.,
This study demonstrated that prucalopride starting from 4 weeks till the end of 12 weeks showed improvements in stool frequency and consistency and reduced the urge for straining at defecation to that of placebo. The test group patients achieved significantly (P ≤ 0.001) higher percentage of changes in primary efficacy endpoint of three or more SCBMs than placebo. This efficacy endpoint involved both subjective (spontaneous evacuation) and objective components (number of movements) giving significant meaning to it. In our setup, there was a 1.57 increase in SCBM per week in the prucalopride arm compared to 1.1 in the placebo arm. At 12 weeks, percentage of patients with 3 or more SCBMs was 31% in the prucalopride arm in contrast to 15% in the placebo arm. The patients in the prucalopride arm (39%) had 3 or more SBMs per week as compared to placebo (19%) at end of 12 weeks (P ≤ 0.001). The response rates among patients, when followed through 4–8 weeks, were highly significant (P ≤ 0.001) in the prucalopride arm (42%) than placebo (17%). Patients in the prucalopride arm through 8–12 weeks reported less use of rescue medication (bisacodyl tablets) than placebo (P ≤ 0.05, in all cases). These findings were consistently demonstrated in several studies.,,,
Other secondary efficacy endpoints like improvement and relief in CC symptoms validated via the Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaire at baseline, 4, 8, and 12 weeks were significantly high (P ≤ 0.001) in the prucalopride arm than in the placebo arm. One-point improvement in the overall PAC-SYM score and its subsymptom scores from baseline were more pronounced in the test arm than placebo, which was in concordance to study done by Camilleri et al., Quigley et al., Tack et al.,,,, and Lin et al.
At 12 weeks, 87% of patients in the test arm had improved stool consistency scores (BSS 3 and 4) as measured by the Bristol Stool Scale in contrast to 42% of patients in the placebo arm.,, Treatment satisfaction among patients as measured by a 5-point Likert scale was higher in test arm (highly satisfied = 25%) than in placebo (highly satisfied = 5%) similar studies done by Camilleri et al.,,
Prucalopride was generally well tolerated for 12 weeks of our study period. Adverse events recorded were mostly GI symptoms, mild to moderate in severity within the known pharmacological side effect profile of our study drug.,,, Headache and diarrhea were mostly reported from the Prucalopride arm with the incidence of nausea, flatulence, and bloating side effects being equal in both groups. Diarrhea was mild, transient, and self-limiting owing to prucalopride's mechanism of action. No new safety signal was detected during our study period. No clinically relevant abnormal laboratory or cardiovascular parameters with the therapeutic dose of Prucalopride was reported during the study period, which is in line with studies done by Camilleri et al. and Quigley et al.,
Limitations of our study included a small sample size with a single-centric approach and a duration of only 12 weeks. Further trials with different doses of prucalopride on the Indian population are required to establish a high margin efficacy and safety profile.
| » Conclusion|| |
In coming times, with increasing westernized lifestyle adaptation, dietary habit changes, and rampant use of available CC treatment options, refractoriness to standard pharmacological or nonpharmacological therapeutic options in the Indian subpopulation is going to degrade the productivity and quality of life of constipation patients. Results of our study, 1st of a kind in India, can be extrapolated to the clinical scenario and prucalopride (2 mg) once daily may be considered a treatment option along with dietary and lifestyle modification for chronic, laxative refractory constipation cases.
Further large clinical trials involving a wide array of constipation patients across all ages, e.g., chronic idiopathic constipation in pediatric and geriatric populations, constipation with irritable bowel syndrome, drug-induced constipation(opioids), and motility disorders like postoperative ileus cases are needed to evaluate the long-term effects of prucalopride.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]