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van der Zande JMJ, Koppen IJN, Di Lorenzo C, Lu PL, Benninga MA. Pharmacological treatment for children with constipation: present and future. Expert Opin Pharmacother 2025; 26:519-524. [PMID: 39993939 DOI: 10.1080/14656566.2025.2471524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 02/20/2025] [Indexed: 02/26/2025]
Affiliation(s)
- Julia M J van der Zande
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Pediatric Gastroenterology and Nutrition, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Ilan J N Koppen
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Carlo Di Lorenzo
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
| | - Peter L Lu
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
| | - Marc A Benninga
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
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Kilgore AL, Rogers Boruta MK, Ambartsumyan L, Suarez RG, Patel D, Wood RJ, Darbari A, Rodriguez L. Evaluation and management of pediatric refractory constipation: Recommendations from the NASPGHAN neurogastroenterology and motility committee. J Pediatr Gastroenterol Nutr 2025; 80:353-373. [PMID: 39741384 DOI: 10.1002/jpn3.12390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 08/21/2024] [Accepted: 10/01/2024] [Indexed: 01/03/2025]
Abstract
Refractory constipation (RC) in pediatric patients should be recognized as a distinct condition with long-term impacts on patient and family quality of life. RC requires a more targeted diagnostic evaluation and complex management strategy that may involve management by pediatric neurogastroenterology and motility specialists and multidisciplinary teams including surgeons. Currently, there is a lack of a clear definition, evaluation, and management strategies for RC. This is the first North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition position paper to address pediatric RC regarding its definition, evaluation, and management.
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Affiliation(s)
- Alexandra L Kilgore
- Digestive Health Institute, Children's Hospital Colorado, Aurora, Colorado, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | | | - Lusine Ambartsumyan
- Division of Gastroenterology and Hepatology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington, USA
| | - Roberto Gomez Suarez
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nemours Children's Hospital, Orlando, Florida, USA
| | - Dhiren Patel
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cardinal Glennon Children's Medical Center, Saint Louis University School of Medicine, St Louis, Missouri, USA
| | - Richard J Wood
- Department of Pediatric Colorectal and Pelvic Reconstructive Surgery, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Anil Darbari
- Pediatric Gastroenterology, Department of Pediatrics, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Leonel Rodriguez
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Yale University School of Medicine, New Haven, Connecticut, USA
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Wolfson S, Saps M. Recent advances in treating constipation in children. Expert Rev Gastroenterol Hepatol 2024; 18:325-338. [PMID: 39034812 DOI: 10.1080/17474124.2024.2383636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 07/19/2024] [Indexed: 07/23/2024]
Abstract
INTRODUCTION Functional constipation (FC) is a common childhood condition, diagnosed via the Rome IV criteria. Standard therapy includes lifestyle and dietary modification followed by initiation of osmotic laxative therapy. About 30% of children continue to experience symptoms related to FC despite appropriate management. New pharmacologic, surgical, and neuromodulatory therapies for FC are now available for use in adult and pediatric populations. In 2023, the first pharmacologic agent, linaclotide, obtained FDA approval for treatment of FC in children 6-17 years old. AREAS COVERED This article reviews current and emerging pharmacologic, surgical, and neuromodulation therapies for the management of FC in pediatric patients. Efficacy and safety data regarding each of these modalities was reviewed and discussed. EXPERT OPINION Advancements in therapeutics available for the management of FC necessitate further investigation on safety and efficacy in pediatric populations. Careful consideration should be taken in choosing an available treatment with limited pediatric evidence as adult and pediatric FC have different underlying pathophysiology and require a different therapeutic approach. Standardization of methodology and pediatric endpoints are needed to optimize ability to compare efficacy of different treatments. We predict the future of pediatric FC management will include a personalized approach to care, resulting in improved outcomes.
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Affiliation(s)
- Sharon Wolfson
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Miguel Saps
- Division of Pediatric Gastroenterology,Hepatology and Nutrition, University of Miami, Miami, FL, USA
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van der Zande JMJ, Lu PL. Management of the child with refractory constipation. Aliment Pharmacol Ther 2024; 60 Suppl 1:S42-S53. [PMID: 38923030 DOI: 10.1111/apt.17847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/28/2023] [Accepted: 12/14/2023] [Indexed: 06/28/2024]
Abstract
BACKGROUND Caring for children with constipation refractory to conventional treatment can be challenging and management practices vary widely. AIMS To review recent advances in the evaluation and treatment of children with refractory constipation and to propose an algorithm that incorporates the latest evidence and our institutional experience. METHODS We performed a literature review on diagnostic tests and treatment options for children with refractory constipation. RESULTS Evaluation of a child with refractory constipation seeks to better understand factors contributing to an individual child's presentation. Anorectal manometry evaluating for a rectal evacuation disorder and colonic manometry evaluating for colonic dysmotility can guide subsequent treatment. For the child who has not responded to conventional treatment, a trial of newer medications like linaclotide can be helpful. Transanal irrigation offers a safe and effective alternative for families able to administer daily rectal treatment. Despite mixed evidence in children, pelvic floor biofeedback therapy can help some children with pelvic floor dyssynergia. For younger children unable to cooperate with pelvic floor therapy, or older children with refractory symptoms, internal anal sphincter botulinum toxin injection can be beneficial. Antegrade continence enema treatment can be effective for children with either normal colonic motility or segmental dysmotility. Sacral nerve stimulation is generally reserved for symptoms that persist despite antegrade continence enemas, particularly if faecal incontinence is prominent. In more severe cases, temporary or permanent colonic diversion and segmental colonic resection may be needed. CONCLUSIONS Recent advances offer hope for children with refractory constipation.
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Affiliation(s)
- Julia M J van der Zande
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Peter L Lu
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA
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Di Nardo G, Barbara G, Borrelli O, Cremon C, Giorgio V, Greco L, La Pietra M, Marasco G, Pensabene L, Piccirillo M, Romano C, Salvatore S, Saviano M, Stanghellini V, Strisciuglio C, Tambucci R, Turco R, Zenzeri L, Staiano A. Italian guidelines for the management of irritable bowel syndrome in children and adolescents : Joint Consensus from the Italian Societies of: Gastroenterology, Hepatology and Pediatric Nutrition (SIGENP), Pediatrics (SIP), Gastroenterology and Endoscopy (SIGE) and Neurogastroenterology and Motility (SINGEM). Ital J Pediatr 2024; 50:51. [PMID: 38486305 PMCID: PMC10938778 DOI: 10.1186/s13052-024-01607-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 02/11/2024] [Indexed: 03/18/2024] Open
Abstract
The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID), whose prevalence has widely increased in pediatric population during the past two decades. The exact pathophysiological mechanism underlying IBS is still uncertain, thus resulting in challenging diagnosis and management. Experts from 4 Italian Societies participated in a Delphi consensus, searching medical literature and voting process on 22 statements on both diagnosis and management of IBS in children. Recommendations and levels of evidence were evaluated according to the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was reached for all statements. These guidelines suggest a positive diagnostic strategy within a symptom-based approach, comprehensive of psychological comorbidities assessment, alarm signs and symptoms' exclusion, testing for celiac disease and, under specific circumstances, fecal calprotectin and C-reactive protein. Consensus also suggests to rule out constipation in case of therapeutic failure. Conversely, routine stool testing for enteric pathogens, testing for food allergy/intolerance or small intestinal bacterial overgrowth are not recommended. Colonoscopy is recommended only in patients with alarm features. Regarding treatment, the consensus strongly suggests a dietary approach, psychologically directed therapies and, in specific conditions, gut-brain neuromodulators, under specialist supervision. Conditional recommendation was provided for both probiotics and specific fibers supplementation. Polyethylene glycol achieved consensus recommendation for specific subtypes of IBS. Secretagogues and 5-HT4 agonists are not recommended in children with IBS-C. Certain complementary alternative therapies, antispasmodics and, in specific IBS subtypes, loperamide and rifaximin could be considered.
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Affiliation(s)
- Giovanni Di Nardo
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Pediatric Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Giovanni Barbara
- IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, 40126, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, 40126, Italy
| | - Osvaldo Borrelli
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK
| | - Cesare Cremon
- IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, 40126, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, 40126, Italy
| | - Valentina Giorgio
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luigi Greco
- General Pediatrician, Heath Care Agency of Bergamo, Bergamo, Italy
| | | | - Giovanni Marasco
- IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, 40126, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, 40126, Italy
| | - Licia Pensabene
- Department of Medical and Surgical Sciences, Pediatric Unit, Magna Graecia University, Catanzaro, Italy
| | - Marisa Piccirillo
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Pediatric Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Silvia Salvatore
- Pediatric Department, "F. Del Ponte" Hospital, University of Insubria, Varese, Italy
| | - Michele Saviano
- General Pediatrician, Heath Care Agency of Naples, Naples, Italy
| | - Vincenzo Stanghellini
- IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, 40126, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, 40126, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Renato Tambucci
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Rossella Turco
- Department of Pediatrics, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Letizia Zenzeri
- Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Pediatric Unit, Sant'Andrea University Hospital, Rome, Italy
| | - Annamaria Staiano
- Department of Translational Medical Science, Section of Pediatrics, University Federico II, Via S. Pansini 5, Naples, 80131, Italy.
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Quitadamo P, Tambucci R, Mancini V, Campanozzi A, Caldaro T, Giorgio V, Pensabene L, Isoldi S, Mallardo S, Fusaro F, Staiano A, Salvatore S, Borrelli O. Diagnostic and therapeutic approach to children with chronic refractory constipation: Consensus report by the SIGENP motility working group. Dig Liver Dis 2024; 56:406-420. [PMID: 38104028 DOI: 10.1016/j.dld.2023.11.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 11/15/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023]
Abstract
Constipation is a common problem in children, accounting for about 3% of all primary care visits and up to 25% of referrals to paediatric gastroenterologists. Although polyethylene glycol often proves effective, most children require prolonged treatment and about 50% of them have at least one relapse within the first 5 years after initial recovery. When conventional treatment fails, children are considered to have refractory constipation. Children with refractory constipation deserve specialist management and guidance. Over the last decades, there has been a remarkable increase in our knowledge of normal and abnormal colonic and anorectal motility in children, and a number of different techniques to measure transit and motility have been developed. The present review analyses the possible diagnostic investigations for children with refractory constipation, focusing on their actual indications and their utility in clinical practice. Moreover, we have also analytically reviewed medical and surgical therapeutic options, which should be considered in selected patients in order to achieve the best clinical outcome.
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Affiliation(s)
- Paolo Quitadamo
- Pediatric Gastroenterology and Epatology Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy.
| | - Renato Tambucci
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Valentina Mancini
- Department of Pediatrics and Neonatology, San Carlo Hospital, Milan, Italy
| | - Angelo Campanozzi
- Pediatrics, Department of Medical and Surgical Sciences, University of Foggia
| | - Tamara Caldaro
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Valentina Giorgio
- UOC Pediatria, Fondazione Policlinico Universitario A. Gemelli IRCSS, Roma, Italy
| | - Licia Pensabene
- Department of Medical and Surgical Sciences, Pediatric Unit, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Sara Isoldi
- Pediatric Gastroenterology and Epatology Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy; Maternal and Child Health Department, Sapienza - University of Rome, Santa Maria Goretti Hospital, Polo Pontino, Latina, Italy
| | - Saverio Mallardo
- Maternal and Child Health Department, Sapienza - University of Rome, Santa Maria Goretti Hospital, Polo Pontino, Latina, Italy
| | - Fabio Fusaro
- Department of Medical and Surgical Neonatology, Newborn Surgery Unit, Digestive and Endoscopic Surgery, Gastroenterology and Nutrition, Intestinal Failure Rehabilitation Research Group, Bambino Gesù Children's Hospital Research Institute, Rome, Italy
| | - Annamaria Staiano
- Department of Translational Medical Science, Section of Pediatrics, University "Federico II", Naples, Italy
| | - Silvia Salvatore
- Pediatric Department, Ospedale "F. Del Ponte", University of Insubria, Varese, Italy
| | - Osvaldo Borrelli
- Division of Neurogastroenterology and Motility, Department of Paediatric Gastroenterology, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK
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Velez A, Kaul A, El-Chammas KI, Knowlton L, Madis E, Sahay R, Fei L, Stiehl S, Santucci NR. Safety and Effectiveness of Prucalopride in Children with Functional Constipation with and without Upper Symptoms. Paediatr Drugs 2024; 26:187-195. [PMID: 38175354 PMCID: PMC11114085 DOI: 10.1007/s40272-023-00612-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2023] [Indexed: 01/05/2024]
Abstract
INTRODUCTION Pediatric prucalopride studies for treatment of gastrointestinal (GI) disorders have reported mixed results. We aimed to assess the safety and effectiveness of prucalopride in functional constipation (FC) with and without upper GI symptoms. METHODS Retrospective data on patients with FC receiving combined prucalopride and conventional therapy was compared with those receiving conventional therapy alone within 12 months. Thirty patients on combined therapy and those on conventional therapy were each matched on the basis of age, gender, race, and presence of fecal soiling. Response (complete, partial, or no resolution) was compared. Similarly, response to concurrent functional upper GI symptoms (postprandial pain, bloating, weight loss, vomiting, early satiety, or nausea) and dysphagia, as well as adverse effects, were evaluated in the combined group. RESULTS Mean age of 57 cases was 14.7 ± 4.9 years and 68% were female. Comorbidities included functional upper GI (UGI) symptoms (84%), dysphagia (12%), mood disorders (49%), and hypermobility spectrum disorder (37%). Unmatched cases reported 63% improvement to FC; response did not differ between the matched cohorts (70% versus 76.6%, p = 0.84). Cases showed a 56% improvement in functional UGI symptoms and 100% in dysphagia. Adverse effects were reported in 30%, abdominal cramps being most common. Four (7%) patients with a known mood disorder reported worsened mood, of which two endorsed suicidal ideation. CONCLUSION Prucalopride efficaciously treated concurrent UGI symptoms and dysphagia in constipated pediatric patients and was overall well tolerated. Preexisting mood disorders seemed to worsen in a small subset of cases.
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Affiliation(s)
- Alejandro Velez
- Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Suite T8.382, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Ajay Kaul
- Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Suite T8.382, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
- University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Khalil I El-Chammas
- Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Suite T8.382, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
- University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lesley Knowlton
- Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Suite T8.382, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Erick Madis
- Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Suite T8.382, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Rashmi Sahay
- Biostatistics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Lin Fei
- Biostatistics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Sarah Stiehl
- Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Neha R Santucci
- Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology, Cincinnati Children's Hospital Medical Center, Suite T8.382, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
- University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Cuffari C, Spalding W, Achenbach H, Thakur M, Gabriel A. Design of a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of prucalopride in pediatric patients with functional constipation. Contemp Clin Trials Commun 2023; 33:101144. [PMID: 37215389 PMCID: PMC10192401 DOI: 10.1016/j.conctc.2023.101144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/13/2023] [Accepted: 04/21/2023] [Indexed: 05/24/2023] Open
Abstract
Background A previous phase 3 trial of prucalopride in pediatric patients (6 months-18 years old) with functional constipation (FC) demonstrated no efficacy versus placebo. We designed an additional phase 3 trial to further assess the efficacy, long-term safety and tolerability of prucalopride in children and adolescents. Methods This multicenter trial (ClinicalTrials.gov identifier: NCT04759833; EudraCT number: 2022-003221-22) comprises a 12-week, randomized, double-blind, placebo-controlled phase, followed by a 36-week, double-blind, safety extension phase. Approximately 240 toilet-trained patients aged 3-17 years will be randomized 1:1:1 to receive low- (0.04 mg/kg) or high-dose (0.08 mg/kg) prucalopride, or placebo once daily. Fifteen non-toilet-trained patients ≥6 months old with FC will be included in an exploratory efficacy and safety analysis. Discussion The efficacy endpoints used in this study will differ from those used in adults and in the previous pediatric phase 3 trial; they have been adapted to be more suitable for a wider age range of pediatric patients. Both study phases will be longer than in the previous pediatric study, providing a longer time period in which to assess the efficacy and safety of prucalopride. Study participants will be identified using the modified Rome IV criteria for FC, instead of the Rome III criteria, and non-toilet-trained patients will be included, which will broaden the population of pediatric patients assessed. Patients will undergo fecal disimpaction before randomization and undergo standardized continuous behavioral therapy throughout the trial. This pediatric study of prucalopride will aim to demonstrate the efficacy and long-term safety of this treatment.
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Affiliation(s)
- Carmen Cuffari
- Children's National Hospital, Division of Gastroenterology, Hepatology and Nutrition, Washington, DC, USA
| | | | | | - Manoj Thakur
- Takeda Development Center Americas, Inc., Lexington, MA, USA
| | - André Gabriel
- Takeda Development Center Americas, Inc., Lexington, MA, USA
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Corsello A, Scatigno L, Govoni A, Zuccotti G, Gottrand F, Romano C, Verduci E. Gut dysmotility in children with neurological impairment: the nutritional management. Front Neurol 2023; 14:1200101. [PMID: 37213895 PMCID: PMC10196023 DOI: 10.3389/fneur.2023.1200101] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 04/20/2023] [Indexed: 05/23/2023] Open
Abstract
Intestinal motility disorders represent a frequent problem in children with neurological impairment. These conditions are characterized by abnormal movements of the gut, which can result in symptoms such as constipation, diarrhea, reflux, and vomiting. The underlying mechanisms leading to dysmotility are various, and the clinical manifestations are often nonspecific. Nutritional management is an important aspect of care for children with gut dysmotility, as it can help to improve their quality of life. Oral feeding, when safe and in the absence of risk of ingestion or severe dysphagia, should always be encouraged. When oral nutrition is insufficient or potentially harmful, it is necessary to switch to an enteral by tube or parenteral nutrition before the onset of malnutrition. In most cases, children with severe gut dysmotility may require feeding via a permanent gastrostomy tube to ensure adequate nutrition and hydration. Drugs may be necessary to help manage gut dysmotility, such as laxatives, anticholinergics and prokinetic agents. Nutritional management of patients with neurological impairment often requires an individualized care plan to optimize growth and nutrition and to improve overall health outcomes. This review tries to sum up most significant neurogenetic and neurometabolic disorders associated with gut dysmotility that may require a specific multidisciplinary care, identifying a proposal of nutritional and medical management.
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Affiliation(s)
- Antonio Corsello
- Department of Pediatrics, Vittore Buzzi Children’s Hospital, University of Milan, Milan, Italy
| | - Lorenzo Scatigno
- Department of Pediatrics, Vittore Buzzi Children’s Hospital, University of Milan, Milan, Italy
| | - Annalisa Govoni
- Department of Pediatrics, Vittore Buzzi Children’s Hospital, University of Milan, Milan, Italy
| | - Gianvincenzo Zuccotti
- Department of Pediatrics, Vittore Buzzi Children’s Hospital, University of Milan, Milan, Italy
- Department of Biomedical and Clinical Sciences L. Sacco, University of Milan, Milan, Italy
| | - Frédéric Gottrand
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, CHU Lille, University of Lille, Lille, France
| | - Claudio Romano
- Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Elvira Verduci
- Department of Pediatrics, Vittore Buzzi Children’s Hospital, University of Milan, Milan, Italy
- Department of Health Science, University of Milan, Milan, Italy
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Di Nardo G, Zenzeri L, Guarino M, Molfino A, Parisi P, Barbara G, Stanghellini V, De Giorgio R. Pharmacological and nutritional therapy of children and adults with chronic intestinal pseudo-obstruction. Expert Rev Gastroenterol Hepatol 2023; 17:325-341. [PMID: 36939480 DOI: 10.1080/17474124.2023.2193887] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/18/2023] [Indexed: 03/21/2023]
Abstract
INTRODUCTION Chronic intestinal pseudoobstruction (CIPO) is a rare, heterogenous, and severe form of gastrointestinal dysmotility. AREAS COVERED Pertinent literature on pediatric and adult CIPO management has been assessed via PubMed, Scopus, and EMBASE from inception to June 2022. Prokinetics, aimed at restoring intestinal propulsion (e.g. orthopramides and substituted benzamides, acetyl cholinesterase inhibitors, serotonergic agents, and others), have been poorly tested and the available data showed only partial efficacy. Moreover, some prokinetic agents (e.g. orthopramides and substituted benzamides) can cause major side effects. CIPO-related small intestinal bacterial overgrowth requires treatment preferably via poorly absorbable antibiotics to avoid bacterial resistance. Apart from opioids, which worsen gut motility, analgesics should be considered to manage visceral pain, which might dominate the clinical manifestations. Nutritional support, via modified oral feeding, enteral, or parenteral nutrition, is key to halting CIPO-related malnutrition. EXPERT OPINION There have been significant roadblocks preventing the development of CIPO treatment. Nonetheless, the considerable advancement in neurogastroenterology and pharmacological agents cast hopes to test the actual efficacy of new prokinetics via well-designed clinical trials. Adequate dietary strategies and supplementation remain of crucial importance. Taken together, novel pharmacological and nutritional options are expected to provide adequate treatments forthese patients.
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Affiliation(s)
- Giovanni Di Nardo
- NESMOS Department, Faculty of Medicine & Psychology, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Letizia Zenzeri
- NESMOS Department, Faculty of Medicine & Psychology, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
- Emergency Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Matteo Guarino
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Alessio Molfino
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Pasquale Parisi
- NESMOS Department, Faculty of Medicine & Psychology, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Giovanni Barbara
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria Di Bologna; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Vincenzo Stanghellini
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria Di Bologna; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
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11
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de Geus A, Koppen IJN, Flint RB, Benninga MA, Tabbers MM. An Update of Pharmacological Management in Children with Functional Constipation. Paediatr Drugs 2023; 25:343-358. [PMID: 36941393 PMCID: PMC10097737 DOI: 10.1007/s40272-023-00563-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/19/2023] [Indexed: 03/23/2023]
Abstract
Functional constipation is a common problem in childhood worldwide and has a great impact on social, physical, and emotional functioning of affected children and their caregivers. It is a clinical diagnosis based on the Rome IV criteria. Non-pharmacological treatment involves education, demystification, lifestyle advice, and toilet training. Pharmacological treatment consists of disimpaction, maintenance treatment, and eventually weaning if possible. Polyethylene glycol is considered as the first choice of laxative for both disimpaction and maintenance treatment. Different osmotic laxatives, stimulant laxatives, lubricants, and enemas are available as alternative pharmacological treatment options. Novel drugs are emerging but evidence to support the widespread application of these drugs in the pediatric population is often lacking and more high-quality research is needed in this field. If children remain symptomatic despite optimal pharmacological treatment, botulinum toxin injections in the anal sphincter can be considered as an alternative, more invasive treatment option. This review provides an update on currently available literature concerning the pharmacologic treatment of functional constipation in children.
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Affiliation(s)
- Anna de Geus
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands
| | - Ilan J N Koppen
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands
| | - Robert B Flint
- Department of Clinical Pharmacy, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Division of Neonatology, Department of Paediatrics, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Marc A Benninga
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands
| | - Merit M Tabbers
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Meibergdreef 9, 1105, Amsterdam, AZ, The Netherlands.
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12
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Tran DL, Sintusek P. Functional constipation in children: What physicians should know. World J Gastroenterol 2023; 29:1261-1288. [PMID: 36925458 PMCID: PMC10011959 DOI: 10.3748/wjg.v29.i8.1261] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/05/2022] [Accepted: 02/16/2023] [Indexed: 02/28/2023] Open
Abstract
Functional constipation (FC) is considered the most common functional gastrointestinal disorder in children with a pooled global prevalence of 14.4% (95% confidence interval: 11.2-17.6) when diagnosed based on the Rome IV criteria. Its pathophysiological mechanisms are thought be multifactorial and complicated, resulting in difficult management. Currently, the most effective medication, when used in parallel with toilet training, is osmotic laxatives. Children's adherence to medication and parental concern regarding long-term laxative use are the main contributors to treatment failure. Recently, novel therapies with a high safety profile have been developed, such as probiotics, synbiotics, serotonin 5-hydroxytryptamine 4 receptor agonists, chloride channel activators, and herbal and transitional medicines; nonetheless, well-designed research to support the use of these therapies is needed. This review aims to focus on multiple aspects of FC in children, including global prevalence, pathogenesis, diagnostic criteria, tools, as well as conventional and novel treatment options, such as non-pharmacological management, including adequate fiber and fluid intake, physiotherapy, or neuromodulators. We also report that in very difficult cases, surgical intervention may be required.
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Affiliation(s)
- Duc Long Tran
- Thailand and Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Bangkok, Thailand
- Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho City 9000, Viet Nam
| | - Palittiya Sintusek
- Thai Pediatric Gastroenterology, Hepatology and Immunology Research Unit, Division of Gastroenterology, Department of Pediatrics, King Chulalongkorn Memorial Hospital and Thai Red Cross, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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13
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Hirsch S, Nurko S, Mitchell P, Rosen R. Prucalopride for Treatment of Upper Gastrointestinal Symptoms in Children. Paediatr Drugs 2022; 24:73-81. [PMID: 34950991 PMCID: PMC9531938 DOI: 10.1007/s40272-021-00489-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND Upper gastrointestinal (GI) symptoms are common in pediatrics, and few prokinetics for children exist. The goal of this study was to determine the efficacy of prucalopride for treatment of upper GI symptoms and feeding difficulties in children. METHODS This was a retrospective study of patients prescribed prucalopride for upper GI symptoms at a single tertiary care center from July 2019 to January 2021. Demographic data, the indication for prucalopride, comorbidities, and feeding data were recorded. The primary outcome was improvement in the primary upper GI symptom at first follow-up after prucalopride initiation. Univariable and multivariable analyses were used to assess for factors associated with improvement. RESULTS The final study population included 71 patients who received prucalopride for treatment of upper GI symptoms. The most common indications were nausea (44%), feeding difficulties (20%), and reflux (11%). Patients had a median age of 16.7 years (range 1.9-21.8 years), and they had received 4 ± 4.8 years of care in our GI clinic and trialed 3.0 ± 2.0 other GI medications by the time of the prucalopride prescription. At follow-up 3.6 ± 2.9 months after the prucalopride was prescribed, 46 patients (65%) had symptomatic improvement of the upper GI symptom. Improvement was more likely in patients with enteral tubes (p = 0.04), pulmonary comorbidities (p = 0.006), and neurologic comorbidities (p = 0.02). Amongst patients with feeding difficulties, 79% of patients showed improvements in oral or tube feeding. CONCLUSIONS In this sample of children treated for refractory upper GI symptoms at a single tertiary care center, patients showed improvements in symptoms like nausea, reflux, and feeding difficulties after starting prucalopride.
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Affiliation(s)
- Suzanna Hirsch
- Aerodigestive Center, Center for Motility and Functional Gastrointestinal Disorders, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, 300 Longwood Ave, HUN Ground, Boston, MA, 02115, USA
| | - Samuel Nurko
- Aerodigestive Center, Center for Motility and Functional Gastrointestinal Disorders, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, 300 Longwood Ave, HUN Ground, Boston, MA, 02115, USA
| | - Paul Mitchell
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA
| | - Rachel Rosen
- Aerodigestive Center, Center for Motility and Functional Gastrointestinal Disorders, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, 300 Longwood Ave, HUN Ground, Boston, MA, 02115, USA.
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14
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Arbizu R, Freiberg B, Rodriguez L. Lower Gastrointestinal Functional and Motility Disorders in Children. Pediatr Clin North Am 2021; 68:1255-1271. [PMID: 34736588 DOI: 10.1016/j.pcl.2021.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Functional and motility gastrointestinal disorders are the most common complaints to the pediatric gastroenterologist. Disorders affecting the small intestine carry a significant morbidity and mortality due to the severe limitation of therapeutic interventions available and the complications associated with such interventions. Congenital colorectal disorders are rare but also carry significant morbidity and poor quality of life plus the social stigma associated with its complications. In this review, we summarize the clinical presentation, diagnostic evaluations, and the therapeutic interventions available for the most common and severe gastrointestinal functional and motility disorders of the small bowel, colon, and anorectum.
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Affiliation(s)
- Ricardo Arbizu
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology and Hepatology, Neurogastroenterology and Motility Center, Yale School of Medicine, Yale University School of Medicine, Yale New Haven Children's Hospital, 333 Cedar Street, LMP 4093, PO Box 208064, New Haven, CT 06520, USA
| | - Ben Freiberg
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology and Hepatology, Neurogastroenterology and Motility Center, Yale School of Medicine, Yale University School of Medicine, Yale New Haven Children's Hospital, 333 Cedar Street, LMP 4093, PO Box 208064, New Haven, CT 06520, USA
| | - Leonel Rodriguez
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology and Hepatology, Neurogastroenterology and Motility Center, Yale School of Medicine, Yale University School of Medicine, Yale New Haven Children's Hospital, 333 Cedar Street, LMP 4093, PO Box 208064, New Haven, CT 06520, USA.
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15
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Hussain SZ, Labrum B, Mareya S, Stripling S, Clifford R. Safety of Lubiprostone in Pediatric Patients With Functional Constipation: A Nonrandomized, Open-Label Trial. J Pediatr Gastroenterol Nutr 2021; 73:572-578. [PMID: 34387619 PMCID: PMC8528133 DOI: 10.1097/mpg.0000000000003280] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 07/22/2021] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Pediatric functional constipation (PFC) affects up to 30% of children. Current treatments often do not sustain symptomatic relief. Lubiprostone is a locally acting chloride channel activator that promotes fluid secretion into the small bowel without affecting serum electrolyte concentrations. We assessed the safety/tolerability of oral lubiprostone as treatment for PFC in a 24-week study. METHODS This phase 3 open-label safety trial conducted from April-November 2016 at 13 US sites included patients (ages 6-17 years) diagnosed with PFC (Rome III criteria). Patients <50 and ≥50 kg received lubiprostone 12 or 24 mcg twice daily, respectively, for 24 weeks. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs) and changes from baseline in clinical laboratory parameters and vital signs. RESULTS Overall, 87 patients receiving lubiprostone, 64.3% (36/56) in the 12-mcg group and 54.8% (17/31) in the 24-mcg group, completed the study. Of 12 TEAEs leading to discontinuation, only upper abdominal pain occurred in >1 patient. TEAEs were mostly mild in intensity, with gastrointestinal disorders (diarrhea, vomiting) most frequently reported. No safety concerns were found in vital signs, abbreviated physical examinations, and laboratory tests. Subgroup analyses assessed an impact of age, sex, and race categories on TEAEs and treatment-related adverse events. Mean investigators' assessments of treatment effectiveness (scale of 0-4) for lubiprostone 12- and 24-mcg groups, respectively, were 2.8 and 2.9 at week 12, and 2.7 and 2.2 at week 24. CONCLUSIONS Lubiprostone was well tolerated in the pediatric population. The incidence of TEAEs was comparable to that observed in previous clinical trials and in adults.
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Affiliation(s)
- Sunny Z. Hussain
- Willis-Knighton Pediatric Gastroenterology & Research, Shreveport, LA
| | | | - Shadreck Mareya
- Sucampo Pharmaceuticals (a legal entity of Mallinckrodt Pharmaceuticals), Rockville, MD
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16
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Pesce M, Puoti MG, Rybak A, Andreozzi M, Bruzzese E, Sarnelli G, Borrelli O. Pharmacological interventions for pediatric irritable bowel syndrome. Expert Opin Pharmacother 2021; 23:91-103. [PMID: 34523358 DOI: 10.1080/14656566.2021.1976753] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Irritable bowel syndrome is a common functional gastrointestinal disorder in children, characterized by recurrent abdominal pain associated with altered bowel habits in terms of both frequency and consistency. According to change in stool consistency it is categorized into 4 subtypes. From the etiological perspective, it is a combination of factors takes part in symptoms' generation, the overall treatment response rate is often unsatisfactory if a multidisciplinary is not pursued. AREAS COVERED The aim of this manuscript is to summarize the current pharmacotherapy in pediatric irritable bowel syndrome in order to aid clinicians in treating this challenging disorder. EXPERT OPINION Most evidence involving pediatric populations rely on open label or retrospective studies and/or are not specifically designed for irritable bowel syndrome but tend to generalize their results to mixed populations of children with functional gastrointestinal disorders. A high placebo response rate combined with poor patients' selection could account for the overall weak evidence supporting the use of pharmacological agents in pediatric irritable bowel syndrome. Given the multifaceted nature of the disorder, multidisciplinary approaches combining pharmacotherapy with alternative treatments is highly recommendable.
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Affiliation(s)
- Marcella Pesce
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Maria Giovanna Puoti
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
| | - Anna Rybak
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
| | - Marta Andreozzi
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Eugenia Bruzzese
- Department of Translational Medical Science, University "Federico Ii" of Naples, Naples, Italy
| | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Osvaldo Borrelli
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
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17
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Hasosah M. Chronic Refractory Constipation in Children: Think Beyond Stools. Glob Pediatr Health 2021; 8:2333794X211048739. [PMID: 34616861 PMCID: PMC8488510 DOI: 10.1177/2333794x211048739] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/27/2021] [Accepted: 09/07/2021] [Indexed: 11/15/2022] Open
Abstract
Chronic refractory constipation (CRC) is defined as children who are unable to pass stools in spite of being on maximum laxative therapy and require daily rectal stimulation in the form of enemas or suppositories to pass stools for >3 months. Children are often referred for treatment of refractory constipation that may result from uncontrolled underlying disease or ineffective treatment. Constipated children can be managed by a variety of medical therapeutic options that yield satisfying results in most cases. However, a subset of constipated children fails to benefit from conventional treatments. On treatment failure or on suspicion of organic disease the patient should be referred for further evaluation. Treatment options for treatment-resistant patients are presented. Pharmalogical and non-pharmalogical treatment modalities are reviewed and an algorithm for refractory constipation in children are presented.
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Affiliation(s)
- Mohammed Hasosah
- King Saud Bin Abdulaziz University for Health Sciences, National Guard Hospital, Jeddah, Saudi Arabia
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18
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Sathe M, Moshiree B, Vu PT, Khan U, Heltshe SL, Romasco M, Freedman SD, Schwarzenberg SJ, Goss CH, Freeman AJ. Utilization of electronic patient-reported outcome measures in cystic fibrosis research: Application to the GALAXY study. J Cyst Fibros 2021; 20:605-611. [PMID: 34305007 DOI: 10.1016/j.jcf.2021.07.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/30/2021] [Accepted: 07/04/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The Food and Drug Administration considers patient-reported outcome measures (PROMs) an essential part of clinical research studies for approval of new drugs and new indications for existing drugs. GALAXY evaluated the feasibility of electronic PROMs (ePROMS) to conduct a comprehensive evaluation of gastrointestinal (GI) symptoms in persons with cystic fibrosis (pwCF). METHODS Three validated GI ePROMs (PAC-SYM, PAGI-SYM and PAC-QOL) were combined with a Stool-Specific questionnaire to make up the GALAXY ePROMs and administered prospectively across 26 CF centers in the United States. The ePROMs were completed at enrollment visit and then electronically at weeks 1, 2 and 4. PwCF at least 2 years and older were eligible for the study. Reminders were only provided by the mobile application during the study window. RESULTS There were 402 participants enrolled in GALAXY. Of those, 169 (42%) were under 18 years old and 193 (48%) were female. The proportion of all follow-up weeks with at least 1 ePROM fully completed was 80%, slightly higher in those ≥18 years of age (82.5%) compared to those <18 years of age (76.5%). When assessing the completion for all 4 ePROMs, the percentage was 77.6%, also higher among those ≥18 year of age (81.5% versus 72.2% for < 18 years of age). CONCLUSION Using ePROMs, our study demonstrated that GI symptoms can be feasibly collected with good reproducibility and with minimal involvement of research coordinator time. This mechanism of symptom collection may provide an efficient tool for future CF trials.
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Affiliation(s)
- Meghana Sathe
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Texas Southwestern/Children's Health, Dallas, TX.
| | - Baha Moshiree
- Division of Gastroenterology, Atrium Health, Charlotte, NC
| | - Phuong T Vu
- Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle WA
| | - Umer Khan
- Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle WA
| | - Sonya L Heltshe
- Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle WA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA
| | - Melita Romasco
- Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle WA
| | - Steven D Freedman
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA
| | | | - Christopher H Goss
- Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle WA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA; Department of Medicine, University of Washington School of Medicine, Seattle, WA
| | - A Jay Freeman
- Division of Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
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Mutalib M, Kammermeier J, Vora R, Borrelli O. Prucalopride in intestinal pseudo obstruction, paediatric experience and systematic review. Acta Gastroenterol Belg 2021; 84:429-434. [PMID: 34599567 DOI: 10.51821/84.3.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Intestinal pseudo obstruction both acute and chronic is an uncommon severe motility disorder that affect both children and adults, can lead to significant morbidity burden and have no standard management strategy. Prucalopride a highly selective serotonin receptor agonist is an effective laxative with reported extra colon action. We aim to report our experience in children with acute and chronic intestinal pseudo obstruction who responded to prucalopride and systemically review the use of prucalopride in intestinal pseudo obstruction. METHODS A report of clinical experience and systemic review of the relevant medical databases to identify the outcome of usage of prucalopride in patients with acute and chronic intestinal pseudo obstruction. Studies meeting the selection criteria were reviewed including abstract only and case reports. RESULTS All reported cases showed clinical response to prucalopride. There were three full text, two abstracts only and three case reports all reporting clinical improvement with prucalopride. CONCLUSION Prucalopride appears to show promising results in children and adults with acute and chronic intestinal pseudo obstruction.
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Affiliation(s)
- M Mutalib
- Department of Paediatric Gastroenterology, Evelina London Children's Hospital, London, UK
| | - J Kammermeier
- Department of Paediatric Gastroenterology, Evelina London Children's Hospital, London, UK
| | - R Vora
- Department of Paediatric Gastroenterology, Evelina London Children's Hospital, London, UK
| | - O Borrelli
- Department of Paediatric Gastroenterology, Great Ormond Street Hospital, London, UK
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20
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Cisapride Use in Pediatric Patients With Intestinal Failure and Its Impact on Progression of Enteral Nutrition. J Pediatr Gastroenterol Nutr 2021; 72:43-48. [PMID: 32740525 DOI: 10.1097/mpg.0000000000002868] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Gastrointestinal dysmotility is common in patients with pediatric intestinal failure (PIF), leading to delays in advancement of enteral nutrition (EN). Few studies have been published regarding the safety and efficacy of cisapride for improvement of enteral tolerance and ability to wean parenteral nutrition. Our objective was to describe a single center experience on the use of cisapride in patients with PIF. METHODS Retrospective chart review of patients was performed. Demographic, intestinal anatomy, and outcome data were collected. Percentage of EN before initiation of cisapride, progression of EN at 3 and 6 months, and ability to wean parenteral nutrition after initiation of cisapride were calculated. RESULTS Prokinetics were used in 61 of 106 patients (56.6%); 29 of 60 patients (48.3%) failed to progress EN on other prokinetics and started on cisapride. Before cisapride the progress of EN plateaued for a mean of 42.3 (standard deviation [SD] 60.2) days. The rate of feed progression was 0.14% (SD 0.19)/day pre-cisapride and 0.69%/day (SD 0.31) after cisapride initiation (P < 0.001). Percentage of EN improved significantly from baseline to 3 months postinitiation (23.9% vs 79.4%, respectively; P < 0.001). Electrocardiogram was performed on initiation of cisapride and after every dose change. Medication was discontinued in 2 of 29 (6.8%). CONCLUSION This retrospective study suggests that cisapride may be beneficial in PIF patients who fail to progress EN on first line prokinetics. The most significant period of improvement occurs within 3 months of cisapride initiation. Cardiac side effects in our cohort were lower than previously reported; however, cardiac monitoring is still recommended.
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21
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Abstract
PURPOSE OF REVIEW Chronic constipation is a common problem that substantially impacts the quality of life of patients and families, healthcare professionals, and resources. The purpose of this review is to discuss the medications that are available for management of chronic constipation, including medications that have been approved by the FDA for adults, other been studied in pediatrics now, and might become available within the upcoming years. RECENT FINDINGS Recent developments in the evaluation of childhood constipation are providing a better understanding into defecation disorders in children and not only new therapies are becoming available, including medications, but also other therapies, such as biofeedback for treatment of functional defecation disorders, electrical stimulation, and surgeries. The aim of this article is to provide an update on the medications that are available for management of chronic constipation, especially with the development and study of newer medications, such as Linaclotide and Lubiprostone with promising results in both adult and pediatric patients. SUMMARY This review will help us identify and have a better understanding regarding what medications are available for use and the indications, so that we can better manage patients with chronic constipation. VIDEO ABSTRACT.
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22
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Mutyala R, Sanders K, Bates MD. Assessment and management of pediatric constipation for the primary care clinician. Curr Probl Pediatr Adolesc Health Care 2020; 50:100802. [PMID: 32532657 DOI: 10.1016/j.cppeds.2020.100802] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Constipation is a common problem in pediatrics and accounts for 3-5% of all pediatric office visits and 10-25% of all pediatric gastroenterology referrals. Functional constipation accounts for about 95% of constipation cases, but "red flag" symptoms that suggest organic causes need to be considered. A diagnosis of functional constipation can be made in absence of "red flag" symptoms and a normal physical assessment. Physical assessment should focus on growth, abdominal exam, inspection of the perianal region, and examination of the lumbosacral region. Abdominal x-rays are generally not useful to differentiate between functional and organic causes of constipation. Treatment of constipation includes dietary changes, medication use, and behavioral modification. Osmotic laxatives are used as first-line treatment, and stimulant laxatives can be added if there is no improvement with osmotic laxatives. Despite improvement with laxatives, 40-50% of children with constipation experience at least 1 relapse in 5 years. Quality improvement opportunities exist for improving care of children with functional constipation by specialists partnering with primary care.
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Affiliation(s)
- Ramakrishna Mutyala
- Division of Pediatric Gastroenterology and Nutrition, Dayton Children's Hospital, Dayton, OH 45404, United States; Department of Pediatrics, Boonshoft School of Medicine, Wright State University, Dayton, OH, United States.
| | - Kisandra Sanders
- Division of Pediatric Gastroenterology and Nutrition, Dayton Children's Hospital, Dayton, OH 45404, United States
| | - Michael D Bates
- Division of Pediatric Gastroenterology and Nutrition, Dayton Children's Hospital, Dayton, OH 45404, United States; Department of Pediatrics, Boonshoft School of Medicine, Wright State University, Dayton, OH, United States
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23
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Southwell BR. Treatment of childhood constipation: a synthesis of systematic reviews and meta-analyses. Expert Rev Gastroenterol Hepatol 2020; 14:163-174. [PMID: 32098515 DOI: 10.1080/17474124.2020.1733974] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction: Constipation occurs in many children and can become chronic. Many grow out of it but for one third, it continues into adulthood. For most patients, there is no identifiable organic disorder and it is classified as functional constipation.Areas covered: In 2016, treatment of childhood constipation was extensively reviewed by Rome IV. This review covers meta-analyses and evidence for treatment of paediatric constipation since 2016 and new emerging treatments.Expert opinion: Since 2016, meta-analyses conclude 1) fibre should be included in a normal diet, but further supplementation does not improve constipation; 2) probiotics may increase stool frequency in children, but evidence from larger RCTs is needed; 3) comparing laxatives, polyethylene glycol (PEG) is superior to placebo, lactulose and milk of magnesia, and 4) appendix stomas are effective and should be considered before surgery. Emerging areas of study include food intolerance, electrical stimulation and faecal microbiota transplant. For research, outcome measures need standardising to allow comparison between studies and allow meta-analyses. To assist this, validated GI instruments have been developed by Rome IV and PedsQl.
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Affiliation(s)
- Bridget R Southwell
- Murdoch Children's Research Institute, Urology Department, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
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24
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Vriesman MH, Koppen IJN, Camilleri M, Di Lorenzo C, Benninga MA. Management of functional constipation in children and adults. Nat Rev Gastroenterol Hepatol 2020; 17:21-39. [PMID: 31690829 DOI: 10.1038/s41575-019-0222-y] [Citation(s) in RCA: 245] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/26/2019] [Indexed: 02/06/2023]
Abstract
Functional constipation is common in children and adults worldwide. Functional constipation shows similarities in children and adults, but important differences also exist regarding epidemiology, symptomatology, pathophysiology, diagnostic workup and therapeutic management. In children, the approach focuses on the behavioural nature of the disorder and the initial therapeutic steps involve toilet training and laxatives. In adults, management focuses on excluding an underlying cause and differentiating between different subtypes of functional constipation - normal transit, slow transit or an evacuation disorder - which has important therapeutic consequences. Treatment of adult functional constipation involves lifestyle interventions, pelvic floor interventions (in the presence of a rectal evacuation disorder) and pharmacological therapy. When conventional treatments fail, children and adults are considered to have intractable functional constipation, a troublesome and distressing condition. Intractable constipation is managed with a stepwise approach and in rare cases requires surgical interventions such as antegrade continence enemas in children or colectomy procedures for adults. New drugs, including prokinetic and prosecretory agents, and surgical strategies, such as sacral nerve stimulation, have the potential to improve the management of children and adults with intractable functional constipation.
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Affiliation(s)
- Mana H Vriesman
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
| | - Ilan J N Koppen
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Michael Camilleri
- C.E.N.T.E.R. Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Carlo Di Lorenzo
- Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
| | - Marc A Benninga
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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He Q, Li M, Wang X, Xia Z, Du Y, Li Y, Wei L, Shang J. A simple, efficient and rapid HPLC-UV method for the detection of 5-HT in RIN-14B cell extract and cell culture medium. BMC Chem 2019; 13:76. [PMID: 31384823 PMCID: PMC6661732 DOI: 10.1186/s13065-019-0591-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/31/2019] [Indexed: 12/21/2022] Open
Abstract
5-Hydroxytryptamine (also known as 5-HT, serotonin) is one of the monoamine neurotransmitters which is distributed widely in plasma and brain of mammals and plays important roles in physiological manipulations. In the present method, we describe the development of a simple, efficient and rapid high performance liquid chromatographic method coupled with ultraviolet (HPLC-UV) detector for the qualitative and quantitative analysis of 5-HT in both cell extract and cell culture medium (RIN-14B). The experiments use repeated freeze-thaw cycles followed by centrifugation and direct injection of the supernatant into the chromatography. An analytical C18 column (Agilent Zorbax Extend, 4.6 × 250 mm, 5 μm.) was taken for chromatographic separation; the mobile phase was 0.05 mol/L potassium dihydrogen phosphate (KH2PO4)/acetonitrile (90:10 v/v). Isocratic elution is established at the flow rate of 1.0 mL/min. The time required for this chromatographic run is 8 min. Over the concentration range of 0.1-10 μg/mL, the calibration curve is linear in this method. Other unique characteristics and advantages include high accuracy (92.02-103.28%) and high precision (intra- and inter-day coefficients of variation ≤ 4.69%). This method is applicable for the investigation of drug/condition-response relationships in the function of synthesis and secretion of 5-HT in cultured RIN-14B cells in various in vitro studies.
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Affiliation(s)
- Qiangqiang He
- 0000000119573309grid.9227.eQinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000000119573309grid.9227.eKey Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000 0004 1797 8419grid.410726.6University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Maoru Li
- 0000 0000 9776 7793grid.254147.1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21198 China
- 0000 0000 9776 7793grid.254147.1Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198 China
- 0000 0000 9776 7793grid.254147.1School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 China
| | - Xuechun Wang
- 0000 0000 9776 7793grid.254147.1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21198 China
| | - Zhenjiang Xia
- 0000000119573309grid.9227.eQinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000000119573309grid.9227.eKey Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000 0004 1797 8419grid.410726.6University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Yuzhi Du
- 0000000119573309grid.9227.eQinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000000119573309grid.9227.eKey Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
| | - Yan Li
- 0000000119573309grid.9227.eQinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000000119573309grid.9227.eKey Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000 0004 1797 8419grid.410726.6University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Lixin Wei
- 0000000119573309grid.9227.eQinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000000119573309grid.9227.eKey Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
| | - Jing Shang
- 0000000119573309grid.9227.eQinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000000119573309grid.9227.eKey Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences - Northwest Institute of Plateau Biology, Xining, 810008 Qinghai China
- 0000 0000 9776 7793grid.254147.1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 21198 China
- 0000 0000 9776 7793grid.254147.1Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198 China
- 0000 0000 9776 7793grid.254147.1School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 China
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Daniali M, Nikfar S, Abdollahi M. An overview of the efficacy and safety of prucalopride for the treatment of chronic idiopathic constipation. Expert Opin Pharmacother 2019; 20:2073-2080. [DOI: 10.1080/14656566.2019.1668927] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Marzieh Daniali
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Evidence-Based Evaluation of Cost-Effectiveness and Clinical Outcomes Group, Pharmaceutical Sciences Research Center (PSRC), and the Pharmaceutical Management and Economics Research Center (PMERC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Vijayvargiya P, Camilleri M. Use of prucalopride in adults with chronic idiopathic constipation. Expert Rev Clin Pharmacol 2019; 12:579-589. [PMID: 31096799 DOI: 10.1080/17512433.2019.1620104] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Prucalopride is a selective 5-HT4 receptor agonist with colonic prokinetic activity. It was recently approved by the FDA for the treatment of chronic idiopathic constipation. Before this approval, there were limited options to improve colonic motility in the treatment of chronic idiopathic constipation. Areas covered: We systematically searched PubMed, Embase, ClinicalTrials.gov, and international conference presentations, and we reviewed all studies that evaluated prucalopride for the treatment of chronic idiopathic constipation in adults. In this review, we discuss the pharmacokinetics, pharmacodynamics, receptor interactions, phase I-IV clinical trials, and safety outcomes of prucalopride in adults, including the elderly. Expert opinion: Prucalopride is an effective agent to improve colonic motility, decrease colonic transit time, and increase complete spontaneous bowel movements in patients with chronic idiopathic constipation. Unlike previously available 5-HT4 receptor agonists such as cisapride and tegaserod, prucalopride does not interact with the cardiac hERG potassium channels or other serotonergic receptors in blood vessels and is not associated with an increase in major adverse cardiovascular events. Additionally, prucalopride has demonstrated promise in the treatment of gastroparesis, post-operative ileus, and opioid-induced constipation. Prucalopride directly stimulates colonic motility, differentiating it from all other medications (exclusively osmotic or chloride secretagogues) approved for chronic constipation in the last decade.
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Affiliation(s)
- Priya Vijayvargiya
- a Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Michael Camilleri
- a Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
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Abstract
PURPOSE OF REVIEW Functional constipation (FC) in children is a common health problem with reported worldwide prevalence rates up to 32.2%. The majority of children with constipation respond to oral laxative treatment. After 5 years of intensive treatment, however, approximately 50% of children remain symptomatic. To discuss the evidence for new treatments in these children, including pre- and probiotics, pelvic physiotherapy, prucalopride, sacral nerve stimulation, and surgery, and to highlight the controversies surrounding them. RECENT FINDINGS Pre- and probiotics and prucalopride are not effective in the treatment of childhood constipation. Pelvic physiotherapy and sacral nerve stimulation are promising treatment options but larger trials are needed. Surgery for pediatric constipation is the treatment of last resort. Large, well-designed placebo-controlled trials with proper outcome measures, as suggested by the Rome foundation pediatric subcommittee on clinical trials, are necessary to provide more insight regarding the efficacy of new treatments in childhood constipation.
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Tameez Ud Din A, Khan AH, Bajwa H, Maqsood MH, Malik MN. Clinical Efficacy and Safety Profile of Prucalopride in Chronic Idiopathic Constipation. Cureus 2019; 11:e4382. [PMID: 31218146 PMCID: PMC6553670 DOI: 10.7759/cureus.4382] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 04/03/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic idiopathic constipation (CIC) can be defined as bowel movements that are difficult to pass, are not occurring frequently, or have incomplete evacuation during defecation. A high-fiber diet and laxatives are the commonly used treatments, but in many cases, they do not produce satisfactory results. The first line of treatment is osmotic laxatives. If there is no improvement, the second line is guanylate cyclase-C (GCC) agonists like linaclotide or prokinetic agents such as prucalopride. On December 14, 2018, the United States Food and Drug Administration (US FDA) approved prucalopride for treating chronic idiopathic constipation. Prucalopride is a prokinetic agent which works at the 5-hydroxytryptamine receptor 4 (5-HT4) as an agonist with greater receptor selectivity. Patients on prucalopride reported improved symptoms, quality of life and satisfaction. The most frequent adverse events were headaches and problems related to the gastrointestinal tract. Caution should be taken when using prucalopride in patients with impaired liver and renal function. In Canada, prucalopride has been approved for treatment of female patients with chronic idiopathic constipation who have failed therapy with at least two laxatives from different classes over a six-month period.
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Affiliation(s)
| | - Ameer H Khan
- Internal Medicine, Allama Iqbal Medical College, Lahore, PAK
| | - Hamza Bajwa
- Internal Medicine, King Edward Medical University / Mayo Hospital, Lahore, PAK
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Abstract
Constipation is a common problem in children. Although most children respond to conventional treatment, symptoms persist in a minority. For children with refractory constipation, anorectal and colonic manometry testing can identify a rectal evacuation disorder or colonic motility disorder and guide subsequent management. Novel medications used in adults with constipation are beginning to be used in children, with promising results. Biofeedback therapy and anal sphincter botulinum toxin injection can be considered for children with a rectal evacuation disorder. Surgical management of constipation includes the use of antegrade continence enemas, sacral nerve stimulation, and colonic resection.
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Affiliation(s)
- Peter L Lu
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
| | - Hayat M Mousa
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California, San Diego, Rady Children's Hospital, 3030 Children's Way, San Diego, CA 92123, USA
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Aqueous Extracts of Herba Cistanche Promoted Intestinal Motility in Loperamide-Induced Constipation Rats by Ameliorating the Interstitial Cells of Cajal. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:6236904. [PMID: 29445412 PMCID: PMC5763204 DOI: 10.1155/2017/6236904] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 10/05/2017] [Accepted: 10/25/2017] [Indexed: 12/20/2022]
Abstract
Traditional Chinese medicine was reported to have good effects in treating functional constipation. This work attempted to prove the effects of aqueous extracts of Herba Cistanche (AEHC) on STC treatment and to determine the possible mechanisms by a loperamide-induced slow transit constipation (STC) model. HPLC was performed for identification and confirmation of the bioactive components in the AEHC. It was found that AEHC attenuated STC responses based on increased fecal quantity, moisture content, and intestinal transit rate, as well as serum levels of GAS, MTL, SS, and CGRP. The protein and mRNA levels of c-kit, a labeling of interstitial cells of Cajal (ICC), also increased. Meanwhile, only the protein level of SCF, a ligand of c-kit, increased. The analysis of our data suggested that AEHC could obviously improve the function of ICC via a signaling pathway involving PI3K, SCF, and c-kit and enhance colonic motility indices such as GAS, MTL, SS, and CGRP. It is interesting to note that AEHC appeared to be effective on constipation, so further experiments are necessary to clarify the exact mechanisms involved.
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Omer A, Quigley EMM. An update on prucalopride in the treatment of chronic constipation. Therap Adv Gastroenterol 2017; 10:877-887. [PMID: 29147138 PMCID: PMC5673021 DOI: 10.1177/1756283x17734809] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 08/31/2017] [Indexed: 02/04/2023] Open
Abstract
Chronic constipation (CC) is a highly prevalent and often under-appreciated gastrointestinal disorder associated with significant impairment in quality of life. Symptoms of constipation are typically present for a number of years prior to a patient seeking help. Lifestyle modifications followed by, or coupled with, over-the-counter laxatives represent the initial treatment option; however, relief for many is limited and dissatisfaction rates for these approaches remain high. Over recent years, therefore, considerable effort has been exerted on the development of novel pharmacological approaches. Two major targets have emerged, motility and secretion. Research on the former led to the development of a number of prokinetic agents capable of stimulating colonic motility and, thus, accelerating colonic transit. Of these, earlier prototypes such as cisapride and tegaserod, though effective, were ultimately withdrawn due to cardiovascular adverse events due in part to receptor non-selectivity. Highly selective serotonergic receptor agonists have since emerged which appear to be equally effective in stimulating gut motility but are devoid of cardiac side effects. One such agent is prucalopride, which has now been approved for the management of chronic idiopathic constipation in several countries, but not in the United States. Multiple multicenter, randomized placebo-controlled clinical trials have demonstrated superiority for prucalopride compared to placebo in the short to medium term in relieving the major symptoms of constipation in both men and women across a broad spectrum of ages, ethnicities and geographic locations. To date, prucalopride has enjoyed a favorable safety profile and there have been no signals to suggest arrythmogenicity. Efficacy over longer periods of treatment remains to be confirmed. Evidence for efficacy in other forms of constipation, such as opioid-induced constipation and that related to Parkinson's disease is beginning to emerge; its status in the management of constipation-predominant irritable bowel syndrome or foregut motility disorders, such as gastroparesis, remains to be established.
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Affiliation(s)
- Anam Omer
- Lynda K. and David M. Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, The Methodist Hospital, 6550 Fannin St, SM 1201, Houston, TX 77030, USA
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Levy EI, Lemmens R, Vandenplas Y, Devreker T. Functional constipation in children: challenges and solutions. PEDIATRIC HEALTH MEDICINE AND THERAPEUTICS 2017; 8:19-27. [PMID: 29388621 PMCID: PMC5774595 DOI: 10.2147/phmt.s110940] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
This review intends to update what is known about and what is still a challenge in functional constipation (FC) in children regarding epidemiology, pathophysiology, diagnosis, and management. Although FC is a common childhood problem, its global burden remains unknown as data from parts of the world are missing. Another problem is that there is a large variation in prevalence due to differences in study methods and defining age groups. The pathophysiology of FC remains unclear to date but is probably multifactorial. Withholding behavior is likely to be the most important factor in toddlers and young children. Genetics may also play a role since many patients have positive family history, but mutations in genes associated with FC have not been found. Over the past years, different diagnostic criteria for FC in infants and children have been proposed. This year, Rome IV criteria have been released. Compared to Rome III, it eliminates two diagnostic criteria in children under the age of 4 who still wear diapers. Physical examination and taking a thorough medical history are recommended, but other investigations such as abdominal radiography, transabdominal recto-ultrasonography, colonic transit time, rectal biopsies, and colon manometry are not routinely recommended. Regarding treatment, guidelines recommend disimpaction and maintenance therapy with polyethylene glycol (PEG) with or without electrolytes. But experience shows that acceptability, adherence, and tolerance to PEG are still a challenge. Counseling of parents and children about causes of FC is often neglected. Recent studies suggest that behavior therapy added to laxative therapy improves the relief of symptoms. Further homogeneous studies, better-defined outcomes, and studies conducted in primary care are needed.
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Affiliation(s)
- Elvira Ingrid Levy
- Kidz Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Roel Lemmens
- Kidz Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Yvan Vandenplas
- Kidz Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Thierry Devreker
- Kidz Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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Abstract
PURPOSE There is a scarcity of literature, and prevalent misconceptions about constipation in India. METHODS A literature search in PubMed was conducted with regard to epidemiology, clinical features, and management of constipation. Special emphasis was paid to functional constipation and refractory constipation. English language studies available full text over the last 25 years were considered and relevant information was extracted. CONCLUSIONS Estimated prevalence of constipation is 3% among toddlers and pre-school children worldwide and 95%, of them are considered functional. A careful history and thorough physical examination is all that is required to diagnose functional constipation. Management includes disimpaction followed by maintenance therapy with oral laxative, dietary modification and toilet training. A close and regular follow-up is necessary for successful treatment. In most of the cases laxative needs to be continued for several months and sometimes years. Early withdrawal of laxative is the commonest cause of recurrence. Refractory constipation is less common in primary care set up. Radiological colon transit study is useful in picking up Slow transit constipation. Antegrade continence enema plays an important role in the management of slow transit constipation.
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Abstract
Prucalopride (Resolor®), a highly selective serotonin 5-HT4 receptor agonist, is indicated in the European Economic Area for the treatment of adults with chronic idiopathic constipation (CIC) in whom laxatives have failed to provide adequate relief. This article reviews the pharmacological properties of prucalopride and its clinical efficacy and tolerability in patients with CIC. In five well-designed, 12-week trials in patients with CIC, oral prucalopride 2 mg/day was significantly more effective than placebo at improving bowel function, including the number of bowel movements and a range of other constipation symptoms, as well as health-related quality of life and patient satisfaction; however, no significant differences in bowel function measures were observed between prucalopride and placebo in a 24-week trial. Oral PEG-3350 + electrolytes reconstituted powder was found to be noninferior but not superior to prucalopride according to primary endpoint data from a 4-week, controlled-environment trial. Prucalopride was generally well tolerated in clinical trials; the most common adverse events were headache, diarrhoea, nausea and abdominal pain. No cardiovascular safety issues have arisen with prucalopride treatment. Although further long-term and comparative data would be beneficial, prucalopride provides an additional treatment option for patients with CIC.
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Koppen IJN, Di Lorenzo C, Saps M, Dinning PG, Yacob D, Levitt MA, Benninga MA. Childhood constipation: finally something is moving! Expert Rev Gastroenterol Hepatol 2016; 10:141-55. [PMID: 26466201 DOI: 10.1586/17474124.2016.1098533] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent developments in the evaluation and treatment of childhood constipation are likely to influence the way we deal with pediatric defecation disorders in the near future. Innovations in both colonic and anorectal manometry are leading to novel insights into functional defecation disorders in children. Promising results have been achieved with innovative therapies such as electrical stimulation and new drugs with targets that differ from conventional pharmacological treatments. Also, new surgical approaches, guided by manometric findings, have led to improvement in patient outcome. Finally, utilization of non-pharmacological interventions such as fiber and probiotics has been a field of particular interest in recent years. The aim of this article is to provide an update on these and other novel diagnostic and therapeutic tools related to childhood constipation.
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Affiliation(s)
- Ilan J N Koppen
- a Department of Pediatric Gastroenterology and Nutrition , Emma Children's Hospital/Academic Medical Center , Amsterdam , The Netherlands.,b Division of Pediatric Gastroenterology, Hepatology, and Nutrition , Nationwide Children's Hospital , Columbus , OH , USA
| | - Carlo Di Lorenzo
- b Division of Pediatric Gastroenterology, Hepatology, and Nutrition , Nationwide Children's Hospital , Columbus , OH , USA
| | - Miguel Saps
- b Division of Pediatric Gastroenterology, Hepatology, and Nutrition , Nationwide Children's Hospital , Columbus , OH , USA
| | - Phil G Dinning
- c Departments of Gastroenterology & Surgery , Flinders Medical Centre, Flinders University , South Australia , Australia
| | - Desale Yacob
- b Division of Pediatric Gastroenterology, Hepatology, and Nutrition , Nationwide Children's Hospital , Columbus , OH , USA
| | - Marc A Levitt
- d Center for Colorectal and Pelvic Reconstruction, Nationwide Children's Hospital, Department of Surgery , The Ohio State University , Columbus , OH , USA
| | - Marc A Benninga
- a Department of Pediatric Gastroenterology and Nutrition , Emma Children's Hospital/Academic Medical Center , Amsterdam , The Netherlands
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van Schaick E, Benninga MA, Levine A, Magnusson M, Troy S. Development of a population pharmacokinetic model of prucalopride in children with functional constipation. Pharmacol Res Perspect 2016; 4:e00236. [PMID: 27891230 PMCID: PMC5114692 DOI: 10.1002/prp2.236] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 03/16/2016] [Accepted: 03/18/2016] [Indexed: 11/10/2022] Open
Abstract
A recent phase 3 trial of prucalopride in children with functional constipation (SPD555-303 ClinicalTrials.gov Identifier: NCT01330381) reported negative efficacy results. Here, we developed a population pharmacokinetic (PK) model of prucalopride in children to assess prucalopride exposure in SPD555-303. An initial population PK model in children was developed based on sampled single-dose data from a phase 1 study (PRU-USA-12). This model was subsequently updated with sampled data from SPD555-303 and used to simulate plasma concentration-time profiles for children aged 6 months to 18 years who were treated once daily with prucalopride 0.02, 0.04, or 0.06 mg kg-1 (maximum dose, 2 mg). Simulated PK profiles were compared with those of adults at the recommended dose of 2 mg once daily. Data were available from 38 patients (median age, 8.5 years) in PRU-USA-12 and 137 patients (median age, 7.9 years) in SPD555-303. Mean (range) area under the plasma concentration-time curve (AUC) at steady state was 62.3 (40.5-82.7) ng mL-1 h (dose, 0.03 mg kg-1) in PRU-USA-12 and 100.3 (22.7-286.0) ng mL-1 h (dose, 0.04 mg kg-1; maximum, 2 mg) in SPD555-303. Prucalopride 0.04 mg kg-1 once daily in children produced similar maximum plasma concentrations and approximately 10% lower AUC compared with adults receiving 2 mg once daily. This population PK analysis indicates that the PK profile of prucalopride in children in SPD555-303 was similar to that observed in adults. The negative efficacy results of SPD555-303 cannot be explained by differences in prucalopride exposure between children and adults.
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Affiliation(s)
| | - Marc A. Benninga
- Division of Pediatric Gastroenterology and NutritionEmma Children's Hospital/Academic Medical CenterAmsterdamNetherland
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Paul SP, Broad SR, Spray C. Idiopathic constipation in children clinical practice guidelines. Arch Dis Child Educ Pract Ed 2016; 101:65-9. [PMID: 26276787 DOI: 10.1136/archdischild-2014-307956] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 07/16/2015] [Indexed: 12/22/2022]
Affiliation(s)
- Siba Prosad Paul
- Department of Paediatric Gastroenterology, Bristol Royal Hospital for Children, Bristol, UK
| | - Samuel Robin Broad
- Department of Paediatric Gastroenterology, Bristol Royal Hospital for Children, Bristol, UK
| | - Christine Spray
- Department of Paediatric Gastroenterology, Bristol Royal Hospital for Children, Bristol, UK
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Bassotti G, Gambaccini D, Bellini M. Prucalopride succinate for the treatment of constipation: an update. Expert Rev Gastroenterol Hepatol 2016; 10:291-300. [PMID: 26647167 DOI: 10.1586/17474124.2016.1129897] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Constipation is a disorder frequently complained about by patients in daily clinical practice. However, to date, its treatment is still commonly unsatisfactory, especially concerning patients' quality of life, when using conventional measures. Prucalopride, a selective 5-hydroxytryptamine receptor 4 agonist, was introduced to the market in 2009 and has been commercially available in Europe since 2010. The main effect of prucalopride is to stimulate colonic motility, which explains its efficacy to treat constipated patients unresponsive to other regimens. Literature search was carried out to look for effects of prucalopride on constipated patients. Several papers were found demonstrating that prucalopride is effective in treatment of constipated patients. Due to its few side effects, the lack of cardiovascular effects and interactions with other drugs, prucalopride may be safely used in elderly people as well.
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Affiliation(s)
- Gabrio Bassotti
- a Gastroenterology & Hepatology Section, Department of Medicine , University of Perugia Medical School , Perugia , Italy
| | - Dario Gambaccini
- b Gastrointestinal Unit, Department of Gastroenterology , University of Pisa , Pisa , Italy
| | - Massimo Bellini
- b Gastrointestinal Unit, Department of Gastroenterology , University of Pisa , Pisa , Italy
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Leelakusolvong S, Ke M, Zou D, Choi SC, Tack J, Quigley EMM, Liu A, Kim JY. Factors predictive of treatment-emergent adverse events of prucalopride: an integrated analysis of four randomized, double-blind, placebo-controlled trials. Gut Liver 2015; 9:208-13. [PMID: 25534573 PMCID: PMC4351028 DOI: 10.5009/gnl14290] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background/Aims This integrated analysis aimed to identify the factors associated with the most frequently reported treatment-emergent adverse events (TEAEs) in Asian and non-Asian patients with chronic constipation (CC) who receive prucalopride or placebo over 12 weeks. Methods Pooled data from four randomized, double-blind, placebo-controlled, multicenter, phase III studies (NCT00488137, NCT00483886, NCT00485940, and NCT01116206) on patients treated with prucalopride 2 mg or placebo were analyzed. The associations between predictors and TEAEs were evaluated based on a logistic regression model. Results Overall, 1,821 patients (Asian, 26.1%; non-Asian, 73.9%) were analyzed. Prucalopride treatment was significantly associated with diarrhea, headache, and nausea (p<0.001), but not with abdominal pain, compared with placebo. Differences in the prevalence of TEAEs between prucalopride and placebo decreased greatly after the first day of treatment. Compared with non-Asians, Asians were more likely to experience diarrhea and less likely to develop abdominal pain, headache, and nausea. Prior laxative use, CC duration, and body weight were not predictive of any of these TEAEs. Conclusions Prucalopride treatment was positively associated with diarrhea, headache, and nausea. Asian patients tended to have a higher frequency of diarrhea but lower frequencies of headache, abdominal pain, and nausea compared with non-Asians.
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Affiliation(s)
- Somchai Leelakusolvong
- Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - MeiYun Ke
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Duowu Zou
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Suck Chei Choi
- Division of Gastroenterology, Department of Internal Medicine, Wonkwang University College of Medicine, Digestive Disease Research Institute, Iksan, Korea
| | - Jan Tack
- Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA
| | - Andy Liu
- Department of Statistical Programming, Janssen Research & Development, Shanghai, China
| | - Jin Yong Kim
- Regional Medical Affairs, Janssen Asia-Pacific, Singapore
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Abstract
Functional constipation is a common healthcare problem among children worldwide and accounts for high healthcare usage and costs. Functional constipation is a clinical diagnosis; the evaluation primarily consists of a thorough medical history and a complete physical examination. Additional investigations are not necessary in most cases. Treatment consists of non-pharmacological and pharmacological interventions. Non-pharmacological interventions involve education and demystification, toilet training (with a reward system), and a defecation diary. Pharmacological treatment comprises three steps: disimpaction, maintenance treatment, and weaning. The treatment of first choice is oral laxatives, preferably polyethylene glycol. When this is insufficient, other therapeutic agents are available. This review discusses the evaluation and management of functional constipation in the pediatric population and provides a summary of drug treatment options.
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Affiliation(s)
- Ilan J N Koppen
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Meibergdreef 9, Room C2-312, 1105 AZ, Amsterdam, The Netherlands.
| | - Laureen A Lammers
- Department of Hospital Pharmacy, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Marc A Benninga
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Meibergdreef 9, Room C2-312, 1105 AZ, Amsterdam, The Netherlands
| | - Merit M Tabbers
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Meibergdreef 9, Room C2-312, 1105 AZ, Amsterdam, The Netherlands.
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Diederen K, Mugie SM, Benninga MA. Efficacy and safety of prucalopride in adults and children with chronic constipation. Expert Opin Pharmacother 2014; 16:407-16. [PMID: 25539475 DOI: 10.1517/14656566.2015.996547] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Chronic constipation (CC) is a debilitating condition with high prevalence rates both in children and adults. Despite the broad range of medical and pharmaceutical treatments, the bowel function does not restore in a fair amount of patients. Prucalopride is a first-in-class selective, high affinity serotonin 5-hydroxytryptamine type 4 (5-HT4) receptor agonist promoting gastro-intestinal prokinetic activity and has been evaluated for the treatment of CC. AREAS COVERED A PubMed search (1965 - 2014) using the following terms alone or in combination: prucalopride, 5-HT4, R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, human ether-a-go-go related gene (hERG), arrhythmia, potassium current, elderly, children. EXPERT OPINION Prucalopride, a highly selective 5-HT4 receptor agonist, stimulates gastrointestinal motility and has been proven to be effective in the treatment of CC in adults by increasing stool frequency, reducing constipation-related symptoms and improving quality of life (QoL). The safety and tolerability have been proven to be excellent. More research would be preferable on the effect of prucalopride on men, children and in other gastrointestinal motility disorders.
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Affiliation(s)
- Kay Diederen
- Emma Children's Hospital, Academic Medical Centre, Department of Paediatric Gastroenterology and Nutrition , Meibergdreef 9, 1105 AZ Amsterdam , The Netherlands +31 20 5665270 ; +31 20 6917033 ;
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Mugie SM, Korczowski B, Bodi P, Green A, Kerstens R, Ausma J, Ruth M, Levine A, Benninga MA. Prucalopride is no more effective than placebo for children with functional constipation. Gastroenterology 2014; 147:1285-95.e1. [PMID: 25239590 DOI: 10.1053/j.gastro.2014.09.005] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 08/12/2014] [Accepted: 09/01/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Prucalopride is a selective, high-affinity agonist of the 5-hydroxytryptamine (serotonin) receptor 4 that enhances motility in the gastrointestinal tract. We performed a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of prucalopride in children (6 months to 18 years old) with functional constipation. METHODS Children with functional constipation, based on the Rome III criteria, were given prucalopride (children ≤ 50 kg were given a 0.04 mg/kg oral solution; children >50 kg were given a 2-mg tablet) or placebo once daily for 8 weeks. The primary efficacy end point was the proportion of children with toileting skills who had a mean of ≥ 3 spontaneous bowel movements/week and ≤ 1 episode of fecal incontinence/2 weeks, from study weeks 5-8 (responders). Adverse events, clinical laboratory values, and electrocardiograms were monitored. RESULTS Efficacy and safety were assessed in 213 children (106 prucalopride, 107 placebo). Twenty-five percent were younger than 4 years old, 50% were 4-11 years old, and 25% were 12-18 years old; 55.4% were girls. At screening, 62.3% of patients in the prucalopride group and 55.1% in the placebo group had a history of fecal incontinence; 60.4% and 55.1% in the prucalopride and placebo groups, respectively, had a mean of ≤ 1 spontaneous bowel movements/week. The proportion of responders was similar between groups (prucalopride, 17.0% and placebo, 17.8%). There were no statistically significant differences in the primary efficacy end point when patients were stratified by sex, age group, or country. The incidence of treatment-emergent adverse events was similar in the prucalopride (69.8%) and placebo (60.7%) groups. CONCLUSIONS Prucalopride, although generally well tolerated, was not more effective than placebo in children with functional constipation. ClinicalTrials.gov Number: NCT01330381.
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Affiliation(s)
- Suzanne M Mugie
- Division of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
| | - Bartosz Korczowski
- Pediatric Department, Medical College, University of Rzeszów, Rzeszów, Poland
| | - Piroska Bodi
- Department of Paediatrics, Pándy Kálmán Hospital, Gyula, Hungary
| | | | | | | | | | | | - Marc A Benninga
- Division of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands
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Abstract
The highly selective serotonin 5-HT4 receptor agonist prucalopride (Resolor(®), Resotran(®), Resotrans(®)) is indicated for the treatment of chronic constipation. In four randomized, double-blind, multicentre, 12-week trials in patients (predominantly women) with chronic constipation, oral prucalopride 2 mg once daily improved bowel function to a significantly greater extent than placebo, with a significantly greater proportion of prucalopride than placebo recipients achieving an average of ≥3 spontaneous, complete bowel movements per week (primary endpoint). Significantly greater improvements in health-related quality of life, patient satisfaction with treatment and bowel habit, and a range of constipation-related symptoms were also seen with prucalopride than with placebo. Satisfaction with treatment and bowel habit was maintained with prucalopride in the longer term. Prucalopride was generally well tolerated in patients with chronic constipation, with the most commonly reported adverse events (headache, nausea, abdominal pain, diarrhoea) primarily occurring on the first day of treatment. During the clinical trials, no cardiovascular safety issues have arisen in patients with chronic constipation receiving prucalopride. In conclusion, prucalopride is an important option for use in patients with chronic constipation who have not experienced adequate relief with laxatives.
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Affiliation(s)
- Gillian M Keating
- Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand,
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Corsetti M, Tack J. New pharmacological treatment options for chronic constipation. Expert Opin Pharmacother 2014; 15:927-41. [PMID: 24661106 DOI: 10.1517/14656566.2014.900543] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION A number of new medications were recently demonstrated to be more effective than placebo in treating chronic constipation, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide. Recent publications have also revisited traditional laxatives like PEG. Moreover, a number of pharmacological treatments are in development and these include another guanylate cyclase-C agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat. AREAS COVERED This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat. EXPERT OPINION The possible present or future clinical application of prucalopride, linaclotide, plecanatide and elobixibat in both chronic constipation and irritable bowel syndrome with constipation is reported, and some considerations on the possible role of PEG taking into account recent literature are advanced.
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Affiliation(s)
- Maura Corsetti
- University of Leuven, Translational Research Center for Gastrointestinal Disorders , Herestraat 49, 3000 Leuven , Belgium
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