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Alshehri TK, Alsharif MNS, Asiri LAA, Mukharrib MS, Alzahrani MA. Prevalence and Associated Factors of Irritable Bowel Syndrome among Medical Students at King Khalid University. Ann Afr Med 2024; 24:01244624-990000000-00084. [PMID: 39710606 PMCID: PMC11837827 DOI: 10.4103/aam.aam_14_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 06/13/2020] [Accepted: 08/18/2020] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND The stressful life of medical students might induce or exacerbate irritable bowel syndrome (IBS) symptoms. OBJECTIVES The purpose of this study was to determine the prevalence and related factors of IBS among medical students at King Khalid University (KKU), Saudi Arabia. MATERIALS AND METHODS A descriptive cross-sectional study was conducted among medical students at the KKU. The data collection period was from January to February 2018. Stratified sampling technique was used that included medical students from the second to the sixth year, using self-administered questionnaires contain socio-demographics, medical history, Rome criteria IV, and a personality scale of manifest anxiety. RESULTS The intended participants were 400 medical students (100%) with 363 (90%) respondents. The mean age was 22 ± 1.6 years; there were 52.9% males and 47.1% females. The prevalence rate of IBS according to the Rome IV criteria was 10.7%. Regarding diagnostic criteria for IBS subtypes, 23.1% represented for both IBS with predominant constipation and IBS with predominant diarrhea, IBS with mixed bowel habits, both diarrhea and constipation, are the higher percentage (43.6%), and IBS unclassified subtype represented by 10.3%. Chi-square test showed high correlation between age and smoking and body mass index (P = 0.04 and 0.05, respectively). Further, there is a significant relationship between IBS and anxiety level (P = 0.04). No gender difference was noted. CONCLUSION The prevalence of IBS among medical students at KKU was highest in the age group of 21-23 years, who were nonsmokers, and who had a relatively high grade point average. We did not find a gender difference. Compared to non-IBS students, the anxiety level of the students with IBS was dramatically higher.
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Budriesi R, Corazza I, Roncioni S, Scanferlato R, De Luca D, Marzetti C, Gotti R, Rizzardi N, Bergamini C, Micucci M, Roncarati D, Mattioli LB. Herbal Extracts Mixed with Essential Oils: A Network Approach for Gastric and Intestinal Motility Disorders. Nutrients 2024; 16:4357. [PMID: 39770978 PMCID: PMC11677010 DOI: 10.3390/nu16244357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Three herbal extracts (Asparagus racemosus Willd., Tabebuia avellanedae Lorentz, and Glycyrrhiza glabra L.) were mixed with three essential oils (Foeniculum vulgare Mill., Mentha piperita L., and Pimpinella anisum L.) to formulate a product (HEMEO) whose active compounds include saponins and steroids in Asparagus racemosus, known for their anti-inflammatory properties; glycyrrhizin and flavonoids in Glycyrrhiza glabra, which exhibit gastroprotective and antispasmodic effects; menthol in Mentha piperita, contributing with antispasmodic and antimicrobial properties; and anethole and polyphenols in Pimpinella anisum, which modulate intestinal motility and offer antimicrobial activity. OBJECTIVE HEMEO was formulated for applications in intestinal motility disorders. METHODS HEMEO was evaluated for spontaneous and induced motility effects in isolated guinea pig ileum, colon, and stomach. Ex vivo experiments were conducted using LabChart software v7.0, and the product's antibacterial action against Helicobacter pylori and its antioxidant effects were assessed through disc diffusion and FRAP assays. The presence of the volatile compounds in the formulation was confirmed by GC-MS analysis; the TPC of HEMEO, determined using the Folin-Ciocalteu method, was 9.925 ± 0.42 mg GAE/g. CONCLUSIONS HEMEO showed a phenolic content correlated with its antioxidant potential and in addition inhibited H. pylori growth and demonstrated notable antioxidant properties, suggesting its role as a supportive agent in digestive processes and in managing motility disorders.
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Affiliation(s)
- Roberta Budriesi
- Food Chemistry and Nutraceutical Laboratory, Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy;
| | - Ivan Corazza
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40138 Bologna, Italy;
| | - Simone Roncioni
- Valsambro S.r.l., 40121 Bologna, Italy; (S.R.); (R.S.); (D.D.L.); (C.M.)
| | | | - Dalila De Luca
- Valsambro S.r.l., 40121 Bologna, Italy; (S.R.); (R.S.); (D.D.L.); (C.M.)
| | - Carla Marzetti
- Valsambro S.r.l., 40121 Bologna, Italy; (S.R.); (R.S.); (D.D.L.); (C.M.)
| | - Roberto Gotti
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
| | - Nicola Rizzardi
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (N.R.); (C.B.)
| | - Christian Bergamini
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (N.R.); (C.B.)
| | - Matteo Micucci
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61029 Urbino, Italy;
| | - Davide Roncarati
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Via Selmi 3, 40126 Bologna, Italy;
| | - Laura Beatrice Mattioli
- Food Chemistry and Nutraceutical Laboratory, Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy;
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Karpuzcu HC, Turan Erdoğan B, Erdoğan Ç. The effect of adding pancreatin to standard otilinium bromide and simethicone treatment in type 2 diabetes mellitus patients with irritable bowel syndrome. Sci Rep 2024; 14:24661. [PMID: 39433866 PMCID: PMC11493971 DOI: 10.1038/s41598-024-74694-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 09/27/2024] [Indexed: 10/23/2024] Open
Abstract
This study aimed to assess the impact of adding pancreatin (a pancreatic enzyme derivative) to standard treatment on patients diagnosed with Irritable Bowel Syndrome (IBS) and Type 2 Diabetes Mellitus (T2DM). IBS and T2DM frequently coexist, leading to significant gastrointestinal symptoms and a decrease in quality of life. Gastrointestinal symptoms arising in T2DM patients present challenges in management for both clinicians and patients. Standard treatments may not fully address these symptoms. Recent studies suggest that pancreatic enzyme replacement therapy may offer additional benefits. This study investigates whether adding pancreatin to standard treatment can improve gastrointestinal outcomes in this patient population. Conducted as a prospective observational study, the research involved patients diagnosed with IBS according to Rome IV criteria and having concomitant T2DM. The patients were divided into two groups: one receiving standard dual treatment (otilinium bromide + simethicone) and the other receiving a triple therapy including a pancreatin derivative in addition to the standard treatment. Various clinical scores and measurements, including Visual Analog Scale (VAS), Bristol Stool Chart (BSC), Irritable Bowel Syndrome-Severity Scoring System (IBS-SSS), and Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL), were assessed before and after treatment. The study comprised 121 patients, with a median age of 41 years (interquartile range [IQR] 38-48), of whom approximately 70.2% were female. Fifty-eight patients (47.9%) received dual therapy, while sixty-three patients (52.1%) received triple therapy. Before treatment, both groups exhibited similar pre-treatment Bristol stool scale results: normal (39.7% and 49.2%) and constipation (37.9% and 31.7%) in the dual and triple therapy subgroups, respectively (p > 0.05). Post-treatment, the triple therapy group showed a significantly higher proportion of normal cases on the Bristol stool scale (82.5%) compared to the dual therapy group (44.8%) (p < 0.001). After treatment, the triple therapy group demonstrated statistically significant improvements in VAS score (p < 0.001), IBS-SSS (p < 0.001), and IBS-QOL (p < 0.001) compared to the dual therapy group. There were no significant differences between groups in BMI, HbA1c levels, duration of diabetes, or diabetes treatment at baseline (p > 0.05 for all parameters). The findings suggest that adding pancreatin to standard therapies significantly enhanced the quality of life for patients with both IBS and T2DM, demonstrating improvements across various symptom measurements and indicating the potential benefits of this supplementary therapy in managing gastrointestinal symptoms in this population. Further studies are warranted to explore its broader clinical implications and mechanisms of action.
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Affiliation(s)
- Hulusi Can Karpuzcu
- Department of Gastroenterology, Ankara Etlik City Hospital, University of Health Sciences, Varlık Mahallesi, Halil Sezai Erkut Caddesi Yenimahalle, Ankara, Turkey.
| | - Beril Turan Erdoğan
- Department of Endocrinology and Metabolism, Ankara City Hospital, Ankara, Turkey
| | - Çağdaş Erdoğan
- Department of Gastroenterology, Ankara Etlik City Hospital, University of Health Sciences, Varlık Mahallesi, Halil Sezai Erkut Caddesi Yenimahalle, Ankara, Turkey
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He L, Yu Z, Geng Z, Huang Z, Zhang C, Dong Y, Gao Y, Wang Y, Chen Q, Sun L, Ma X, Huang B, Wang X, Zhao Y. Structure, gating, and pharmacology of human Ca V3.3 channel. Nat Commun 2022; 13:2084. [PMID: 35440630 PMCID: PMC9019099 DOI: 10.1038/s41467-022-29728-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 03/28/2022] [Indexed: 12/19/2022] Open
Abstract
The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type CaV3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. CaV3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type CaV channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the CaV3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders. T-type calcium channels are implicated in many diseases. Here, multiple structures of CaV3.3 channel elucidate molecular mechanisms of T-type CaV channels activation at low voltage and interaction with different clinically used channel blockers.
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Affiliation(s)
- Lingli He
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhuoya Yu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ze Geng
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.,IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China
| | - Zhuo Huang
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.,IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China
| | - Changjiang Zhang
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yanli Dong
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China
| | - Yiwei Gao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuhang Wang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qihao Chen
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Le Sun
- Beijing Institute of Brain Disorders, Capital Medical University, Beijing, 100069, China
| | - Xinyue Ma
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.,IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China
| | - Bo Huang
- StoneWise Ltd., 1708, Block B, No.19 Zhongguancun Street, Haidian District, Beijing, China
| | - Xiaoqun Wang
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yan Zhao
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. .,State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China. .,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
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Shrivastava A, Mittal A. A Mini Review on Characteristics and Analytical Methods of Otilonium Bromide. Crit Rev Anal Chem 2021; 52:1717-1725. [PMID: 34039224 DOI: 10.1080/10408347.2021.1913983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Irritable bowel syndrome (IBS) is a world-wide disease prevalently in Western nations. It influences about 15% of the western populace, with a negative effect on the quality of life and furthermore on medical services costs. Anticholinergic antispasmodics are first line of treatment for discomfort or abdominal pain, particularly if unrelieved after alleviation of stoppage or antidiarrheal treatment. Otilonium bromide (OTB) is quaternary ammonium compound with action on distal GI tract as antispasmodic. It is utilized in the treatment of patients influenced by Irritable inside disorder (IBS) because of its particular pharmacokinetic and pharmacodynamic properties. OTB is poorly absorbed systematically was viable in contrast with different medications used for same purpose, for example, pinaverium bromide and mebeverine, with a good tolerability profile. The effects are long lasting, even after stopping the dosage regime for reduction of abdominal pain. In this review, an overview of mechanism of action, pharmacologic action, synthesis and particularly various analytical and bioanalytical methods are discussed. The analytical methods discussed are spectrophotometry including Near Infrared Spectroscopy (NIRS), chromatography and capillary electrophoresis methods are described with the range, limit of detection and quantification. The paper also provides details of scope of further extension of analytical methods. It was found that most of the analytical methods involves usage of toxic solvents e.g., methanol, acetonitrile, chloroform etc. posing risk to the analyst as well as environment.
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Affiliation(s)
- Alankar Shrivastava
- Department of Pharmaceutical Quality Assurance, KIET School of Pharmacy, KIET Group of Institutions, Ghaziabad, India
| | - Ashu Mittal
- Department of Pharmaceutics, KIET School of Pharmacy, KIET Group of Institutions, Ghaziabad, India
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Shin SY, Cha BK, Kim WS, Park JY, Kim JW, Choi CH. The Effect of Phloroglucinol in Patients With Diarrhea-predominant Irritable Bowel Syndrome: A Randomized, Double-blind, Placebo-controlled Trial. J Neurogastroenterol Motil 2020; 26:117-127. [PMID: 31917916 PMCID: PMC6955199 DOI: 10.5056/jnm19160] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/24/2019] [Accepted: 11/08/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS We aim to evaluate the efficacy and safety of phloroglucinol in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS Seventy-two patients with IBS-D who met Rome III criteria were 1:1 randomized in a parallel, double-blind design to receive phloroglucinol or placebo for 2 weeks. Patients were followed for 1 week after the end of treatment. The primary outcome was the proportion of responders, defined as those who answered "moderate or more of improvement" to the subject global assessment for at least 1 week of the 2-week treatment period. Secondary outcomes included the proportion of these patients during the 3-week period including 1 week of follow-up, IBS symptoms (abdominal pain/discomfort, diarrhea, urgency, mucus in stool, bloating, and passage of gas), stool frequency and consistency, and IBS quality of life (IBS-QOL). RESULTS The proportion of responders during 2-week treatment period tended to be higher in the phloroglucinol group than in the placebo group, although the difference did not reach statistical significance (55.6% vs 30.6%, P = 0.056). The proportion of responders during the 3-week period was significantly higher in the phloroglucinol group than in the placebo group (61.6% vs 30.6%, P = 0.013). Individual symptom scores, IBS-QOL, stool frequency and consistency tended to improve in the phloroglucinol group, but there were no statistical significances compared to those of the placebo group. No serious adverse events were reported in both groups. CONCLUSIONS Phloroglucinol could be a safe and beneficial option for the management of overall IBS symptoms in patients with IBS-D. Further large scaled studies are warranted.
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Affiliation(s)
- Seung Yong Shin
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul,
Korea
| | - Bong Ki Cha
- Department of Internal Medicine, Chung-Ang Medical Health Care System Hyundae Hospital, Seoul,
Korea
| | - Won-Seok Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul,
Korea
| | - Jae Yong Park
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul,
Korea
| | - Jeong Wook Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul,
Korea
| | - Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul,
Korea
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Munjal A, Dedania B, Cash BD. Current and emerging pharmacological approaches for treating diarrhea-predominant irritable bowel syndrome. Expert Opin Pharmacother 2019; 21:63-71. [PMID: 31738621 DOI: 10.1080/14656566.2019.1691524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Irritable bowel syndrome with diarrhea (IBS-D) is among the most common functional gastrointestinal (GI) disorders and is associated with impaired quality of life, increased health-care utilization, and significant costs to patients and society. The treatment of IBS is typically hierarchal with initial therapies consisting of dietary and lifestyle modifications. Pharmacotherapy with over-the-counter and prescription medications is also commonly used for symptomatic control in the course of therapy.Areas covered: Three medications are approved by the United States Food and Drug Administration (FDA) for IBS-D, with all of them demonstrating efficacy in randomized, placebo-controlled trials. In this review, the authors discuss the clinical trial data applicable to the current FDA approved IBS-D therapies as well as review data related to new and emerging therapies for this condition.Expert opinion: Clinicians should be familiar with emerging therapies for IBS-D as they may provide benefit to some IBS-D patients. The exact mechanisms of action of many of the emerging agents for IBS-D remain unknown. Despite substantial differences and limitations in the design and quality of supporting studies, there is an increasing body of evidence suggesting that emerging agents may promote meaningful symptom improvement in patients with IBS-D.
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Affiliation(s)
- Akhil Munjal
- Division of Internal Medicine, University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA
| | - Bhavtosh Dedania
- Division of Gastroenterology, University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA
| | - Brooks D Cash
- Division of Gastroenterology, University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA
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Lee JH, Kim JI, Baeg MK, Sunwoo YY, Do K, Lee JH, Kim HJ, Choi JS, Kim J, Seo CS, Shin HK, Ha H, Park TY. Effect of Samryungbaekchul-san Combined with Otilonium Bromide on Diarrhea-Predominant Irritable Bowel Syndrome: A Pilot Randomized Controlled Trial. J Clin Med 2019; 8:jcm8101558. [PMID: 31569833 PMCID: PMC6832362 DOI: 10.3390/jcm8101558] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/21/2019] [Accepted: 09/23/2019] [Indexed: 12/12/2022] Open
Abstract
Conventional and herbal drugs are frequently used together to treat many disorders. Samryungbaekchul-san (SRS, a herbal formula) and otilonium bromide (OB, an antispasmodic agent) are widely used to treat diarrhea-predominant irritable bowel syndrome (D-IBS) in Eastern Asian countries. However, there have been no studies on the co-administration of SRS and OB. Therefore, we aimed to preliminarily assess the feasibility of SRS combined with OB for D-IBS treatment in a pilot double-blind, four-arm, parallel-group, randomized controlled trial (RCT), including 80 patients diagnosed with D-IBS according to the Rome III criteria. The patients were randomly assigned to four treatment groups and were administered drugs for eight weeks after a two-week preparatory period. Follow-up was conducted four weeks after the administration period. The primary outcome was evaluated by using a global D-IBS symptom improvement score; no statistically significant difference was observed between the groups. However, multiple logistic regression analysis of primary outcome scores shows that SRS significantly improved D-IBS symptoms (p < 0.05). For secondary outcomes, better results were observed in the SRS + OB group, in terms of symptoms, including abdominal pain, discomfort, frequency of abdominal pain, and stool form than in OB alone or placebo groups (p < 0.05). In conclusion, the co-administration of SRS and OB might be an effective and safe strategy for the treatment of D-IBS. Large-scale RCTs are warranted to further confirm and clarify these findings.
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Affiliation(s)
- Jin-Hyun Lee
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Korea.
| | - Joong Il Kim
- Future Medicine Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Myong Ki Baeg
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Korea.
| | | | - Kwangsun Do
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Korea.
| | - Jung-Han Lee
- Department of Korean Rehabilitation Medicine, Wonkwang University College of Korean Medicine, Iksan 54383, Korea.
| | - Hye-Jung Kim
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Korea.
| | - Ja Sung Choi
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Korea.
| | - Jayoung Kim
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Korea.
| | - Chang-Seob Seo
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Hyeun-Kyoo Shin
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Hyekyung Ha
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
| | - Tae-Yong Park
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary's Hospital, Incheon 22711, Korea.
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Zielińska A, Sałaga M, Włodarczyk M, Fichna J. Chronic abdominal pain in irritable bowel syndrome - current and future therapies. Expert Rev Clin Pharmacol 2018; 11:729-739. [PMID: 29957084 DOI: 10.1080/17512433.2018.1494571] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a functional gut disorder that typically manifests in early adult years. One of the two major symptoms of the disease is chronic, visceral pain. The patients report pain as the most distressing symptom with the greatest impact on quality of life, challenging both to patients and healthcare providers. Areas covered: This review focuses on the pathophysiology of abdominal pain in IBS and describes current treatment possibilities. It also covers latest findings that may lead to novel pharmacological options in IBS pain management. Expert commentary: Pain is the main contributor to severity in IBS. Seeking pain alleviation is the most common reason that IBS sufferers consult with their physicians. Not all patients report being satisfied with available treatments for pain in IBS and there is a pressing need to find new, more efficient therapies for this syndrome.
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Affiliation(s)
- Anna Zielińska
- a Department of Biochemistry, Faculty of Medicine , Medical University of Lodz , Lodz , Poland
| | - Maciej Sałaga
- a Department of Biochemistry, Faculty of Medicine , Medical University of Lodz , Lodz , Poland
| | - Marcin Włodarczyk
- a Department of Biochemistry, Faculty of Medicine , Medical University of Lodz , Lodz , Poland.,b Department of General and Colorectal Surgery, Faculty of Military Medicine , Medical University of Lodz , Lodz , Poland
| | - Jakub Fichna
- a Department of Biochemistry, Faculty of Medicine , Medical University of Lodz , Lodz , Poland
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10
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Lee SH, Jee SR. Effect of antispasmodic agents for the treatment of irritable bowel syndrome. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2018. [DOI: 10.5124/jkma.2018.61.7.428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Sang Heon Lee
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Sam Ryong Jee
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
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Kim JI, Kim P, Lee JH, Kim YJ, Yang NR, Baeg MK, Choi JS, Kim HJ, Kim J, Sunwoo YY, Lee JH, Ha H, Park TY. Effect of herbal extract granules combined with otilonium bromide on irritable bowel syndrome with diarrhoea: a study protocol for a randomised controlled trial. BMJ Open 2017; 7:e018362. [PMID: 29196484 PMCID: PMC5719308 DOI: 10.1136/bmjopen-2017-018362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Irritable bowel syndrome (IBS), known as a functional and organic gastrointestinal disorder, is a collection of symptoms that occur together and generally include pain or discomfort in the abdomen and changes in bowel movement patterns. Due to the limitations of conventional treatments, alternative IBS treatments are used by many patients worldwide. Samryungbaekchulsan (SRS), a herbal formula, has long been used for alleviating diarrhoea-predominant IBS (D-IBS) in traditional Korean medicine. Otilonium bromide (OB) is an antimuscarinic compound used to relieve spasmodic pain in the gut, especially in IBS. Although herbal formulae and Western drugs are commonly coadministered for various diseases in Korea, few clinical studies have been conducted regarding the synergic effects of these treatments for any disease, including D-IBS. METHODS AND ANALYSIS This trial is a randomised, double-blinded, placebo-controlled, double-dummy, four-arm, parallel study. After a 2-week preparation period, 80 patients with D-IBS will be randomly assigned to one of four treatment groups consisting of SRS (water extract granules, 5 g/pack, three times a day) with OB (tablet form, one capsule three times a day) or their placebos, with treatment lasting for 8 weeks. Post-treatment follow-up will be conducted 4 weeks after the end of treatment. The primary outcome is the finding obtained using the Subject's Global Assessment of Relief method. The secondary outcomes are the severity of symptoms related to D-IBS, determined using a 10-point scale, and the change in symptoms. ETHICS AND DISSEMINATION This trial has full ethical approval of the Ethics Committee of Catholic Kwandong University International St. Mary's Hospital (IS15MISV0033) and the Korean Ministry of Food and Drug Safety (30769). The results of the study will be disseminated through a peer-reviewed journal and/or conference presentations. TRIAL PROTOCOL VERSION IS15MISV0033 version 4.0 (25 July 2016). TRIAL REGISTRATION NUMBER KCT0001621 (approval date: 10 August 2015).
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Affiliation(s)
- Joong Il Kim
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Pumsoo Kim
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Jin-Hyun Lee
- Department of Rehabilitation Medicine of Korean Medicine, College of Korean Medicine, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
| | - Yoo-Jin Kim
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Na-rae Yang
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Myong Ki Baeg
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Ja Sung Choi
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Hye-Jung Kim
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Jayoung Kim
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Yun-Young Sunwoo
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
| | - Jung-Han Lee
- Department of Rehabilitation Medicine of Korean Medicine, College of Korean Medicine, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
| | - Hyekyung Ha
- K-herb Research Center, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - Tae-Yong Park
- Institute for Integrative Medicine, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Republic of Korea
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Abstract
BACKGROUND Otilonium bromide (OB) is a spasmolytic agent acting as an L-type calcium channel antagonist in intestinal and colonic smooth muscle cells (SMCs). We analyzed three independent clinical trials with homogeneous design on patients with irritable bowel syndrome (IBS). After 2 weeks receiving placebo, patients were randomized to receive OB (3 × 40 mg daily) or placebo for 15 weeks. We aimed to perform a pooled analysis of the data from these homogeneous clinical trials to evaluate the efficacy of OB treatment on symptoms and global response of patients. METHODS A total of 883 patients with IBS (69.8% women, mean age 46.2 years, 43.8% mixed type) were included, 442 treated with OB and 441 with placebo. The efficacy results from the three studies at weeks 5, 10 and 15 were pooled in an intention-to-treat (ITT) strategy, analyzed with a logistic regression model and described by forest plots. RESULTS Despite a placebo effect in all efficacy variables, a significant therapeutic effect of OB was observed at weeks 10 and 15 with reference to: (a) intensity and frequency of abdominal pain; (b) rate of responders as evaluated by patients (71.8% at week 10 and 77.2% at week 15); (c) severity of bloating; (d) rate of responders as evaluated by physicians (55% at week 10 and 63.9% at week 15). No significant OB effect was observed in stool frequency and consistency. CONCLUSIONS OB is more effective than placebo in IBS treatment. Therapeutic benefits are significant after 10 weeks and are maximal after 15 weeks of treatment.
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Affiliation(s)
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Belgium Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
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Traini C, Evangelista S, Girod V, Faussone-Pellegrini MS, Vannucchi MG. Repeated otilonium bromide administration prevents neurotransmitter changes in colon of rats underwent to wrap restraint stress. J Cell Mol Med 2016; 21:735-745. [PMID: 27866394 PMCID: PMC5345670 DOI: 10.1111/jcmm.13016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 09/14/2016] [Indexed: 12/20/2022] Open
Abstract
Otilonium bromide (OB) is a spasmolytic drug successfully used for the treatment of irritable bowel syndrome (IBS). Its efficacy has been attributed to the block of L- and T-type Ca2+ channels and muscarinic and tachykinin receptors in the smooth muscle. Furthermore, in healthy rats, repeated OB administration modified neurotransmitter expression and function suggesting other mechanisms of action. On this basis, we investigated whether repeated OB treatment prevented the functional and neurochemical changes observed in the colon of rats underwent to wrap restrain stress (WRS) a psychosocial stressor considered suitable to reproduce the main IBS signs and symptoms. In control, WRS and OB/WRS rats functional parameters were measured in vivo and morphological investigations were done ex vivo in the colon. The results showed that OB counteracts most of the neurotransmitters changes caused by WRS. In particular, the drug prevents the decrease in SP-, NK1r-, nNOS-, VIP-, and S100β-immunoreactivity (IR) and the increase in CGRP-, and CRF1r-IR. On the contrary, OB does not affect the increase in CRF2r-IR neurons observed in WRS rats and does not interfere with the mild mucosal inflammation due to WRS. Finally, OB per se increases the Mr2 expression in the muscle wall and decreases the number of the myenteric ChAT-IR neurons. Functional findings show a significantly reduction in the number of spontaneous abdominal contraction in OB treated rats. The ability of OB to block L-type Ca2+ channels, also expressed by enteric neurons, might represent a possible mechanism through which OB exerts its actions.
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Affiliation(s)
- Chiara Traini
- Department of Experimental and Clinical Medicine, Research Unit of Histology and Embryology, Florence, Italy
| | | | | | | | - Maria Giuliana Vannucchi
- Department of Experimental and Clinical Medicine, Research Unit of Histology and Embryology, Florence, Italy
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Vega DR, Halac E, Segovia L, Baggio R. A New, More Stable Polymorphic Form of Otilonium Bromide: Solubility, Crystal Structure, and Phase Transformation. J Pharm Sci 2016; 105:3013-3020. [PMID: 27444388 DOI: 10.1016/j.xphs.2016.06.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 05/06/2016] [Accepted: 06/01/2016] [Indexed: 12/19/2022]
Abstract
A new polymorphic form of otilonium bromide is presented (Form I), and a thorough analysis of its crystal and molecular structure is performed. The compound suffers a temperature-driven first-order phase transition at about 396 K, which transforms it into the polymorph reported by Dapporto P and Sega A (Acta Cryst. 1986;C42:474-478) (Form II). Through thermal analysis and solubility experiments the relative stability of both crystal modifications were determined, confirming that at room temperature this new Form I is the more stable one, Form II existing just in a metastable state.
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Affiliation(s)
- Daniel R Vega
- Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Buenos Aires, Argentina; Escuela de Ciencia y Tecnología, Universidad Nacional General San Martín, Buenos Aires, Argentina
| | - Emilia Halac
- Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Buenos Aires, Argentina; Escuela de Ciencia y Tecnología, Universidad Nacional General San Martín, Buenos Aires, Argentina
| | - Luciano Segovia
- Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Buenos Aires, Argentina
| | - Ricardo Baggio
- Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Buenos Aires, Argentina.
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Eriksson EM, Andrén KI, Kurlberg GK, Eriksson HT. Aspects of the non-pharmacological treatment of irritable bowel syndrome. World J Gastroenterol 2015; 21:11439-11449. [PMID: 26523108 PMCID: PMC4616219 DOI: 10.3748/wjg.v21.i40.11439] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 06/26/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most commonly diagnosed gastrointestinal conditions. It represents a significant healthcare burden and remains a clinical challenge. Over the years IBS has been described from a variety of different perspectives; from a strict illness of the gastrointestinal tract (medical model) to a more complex multi-symptomatic disorder of the brain-gut axis (biopsychosocial/psychosomatic model). In this article we present aspects of the pathophysiology and the non-pharmacological treatment of IBS based on current knowledge. Effects of conditioned stress and/or traumatic influences on the emotional system (top-down) as well as effects on the intestine through stressors, infection, inflammation, food and dysbiosis (bottom-up) can affect brain-gut communication and result in dysregulation of the autonomic nervous system (ANS), playing an important role in the pathophysiology of IBS. Conditioned stress together with dysregulation of the autonomic nervous system and the emotional system may involve reactions in which the distress inside the body is not recognized due to low body awareness. This may explain why patients have difficulty identifying their symptoms despite dysfunction in muscle tension, movement patterns, and posture and biochemical functions in addition to gastrointestinal symptoms. IBS shares many features with other idiopathic conditions, such as fibromyalgia, chronic fatigue syndrome and somatoform disorders. The key to effective treatment is a thorough examination, including a gastroenterological examination to exclude other diseases along with an assessment of body awareness by a body-mind therapist. The literature suggests that early interdisciplinary diagnostic co-operation between gastroenterologists and body-mind therapists is necessary. Re-establishing balance in the ANS is an important component of IBS treatment. This article discusses the current knowledge of body-mind treatment, addressing the topic from a practical point of view.
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Iovino P, Bucci C, Tremolaterra F, Santonicola A, Chiarioni G. Bloating and functional gastro-intestinal disorders: where are we and where are we going? World J Gastroenterol 2014; 20:14407-14419. [PMID: 25339827 PMCID: PMC4202369 DOI: 10.3748/wjg.v20.i39.14407] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 04/07/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
Bloating is one of the most common and bothersome symptoms complained by a large proportion of patients. This symptom has been described with various definitions, such as sensation of a distended abdomen or an abdominal tension or even excessive gas in the abdomen, although bloating should probably be defined as the feeling (e.g. a subjective sensation) of increased pressure within the abdomen. It is usually associated with functional gastrointestinal disorders, like irritable bowel syndrome, but when bloating is not part of another functional bowel or gastrointestinal disorder it is included as an independent entity in Rome III criteria named functional bloating. In terms of diagnosis, major difficulties are due to the lack of measurable parameters to assess and grade this symptom. In addition, it is still unclear to what extent the individual patient complaint of subjective bloating correlates with the objective evidence of abdominal distension. In fact, despite its clinical, social and economic relevance, bloating lacks a clear pathophysiology explanation, and an effective management endorsement, turning this common symptom into a true challenge for both patients and clinicians. Different theories on bloating etiology call into questions an increased luminal contents (gas, stools, liquid or fat) and/or an impaired abdominal empting and/or an altered intra-abdominal volume displacement (abdomino-phrenic theory) and/or an increased perception of intestinal stimuli with a subsequent use of empirical treatments (diet modifications, antibiotics and/or probiotics, prokinetic drugs, antispasmodics, gas reducing agents and tricyclic antidepressants). In this review, our aim was to review the latest knowledge on bloating physiopathology and therapeutic options trying to shed lights on those processes where a clinician could intervene to modify disease course.
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Chmielewska-Wilkoń D, Reggiardo G, Egan CG. Otilonium bromide in irritable bowel syndrome: A dose-ranging randomized double-blind placebo-controlled trial. World J Gastroenterol 2014; 20:12283-12291. [PMID: 25232263 PMCID: PMC4161814 DOI: 10.3748/wjg.v20.i34.12283] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 04/29/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the efficacy and safety of otilonium bromide (OB) in treatment-sensitive functional irritable bowel syndrome (IBS) clinical parameters.
METHODS: Ninety-three patients (44.8 ± 12.6 years, 69% female) with IBS symptoms complying with Rome II criteria participated in this double-blind, placebo-controlled, randomised, dose-ranging phase I/II study. Patients were administered OB 20 mg (n = 24), 40mg (n = 23) and 80 mg (n = 23) tid or placebo (n = 23) in 4 parallel groups for 4 wk. Primary efficacy variables included abdominal discomfort, intestinal habits, number of daily evacuations and stool consistency. Secondary efficacy measures included return to regular intestinal habits and global discomfort. Safety was also assessed.
RESULTS: Baseline clinical characteristics were similar among the 4 groups. Although individual parameters such as intensity and frequency of abdominal discomfort, bloating or pain were reduced by OB over the 4 wk, no significant differences were observed between groups. Similarly, no difference was observed between OB treatment or placebo for mucus in stool and incomplete or difficulty of evacuation. However, evacuation frequency was significantly reduced after 4 wk by 80 mg OB compared to placebo (-8.36% for placebo vs -41.9% for 80 mg OB, P < 0.01). While 21.7% of patients in the placebo group experienced regular intestinal habits after 4 wk, this improvement was greater for patients treated with 40 mg OB (P < 0.01 vs placebo). Furthermore, a dose-dependent reduction in frequency of diarrhoea (χ2-test for trend = 11.5, P < 0.001) and an increase in normal stool frequency was observed. Combining individual variables into a global discomfort index revealed significant improvement among increasing OB doses, favouring 40 mg (P = 0.013) and 80mg OB (P = 0.001) over placebo. No difference was observed between frequency of adverse events for placebo vs OB.
CONCLUSION: This dose-ranging study demonstrates that OB at 40 and 80 mg can improve individual and global clinical symptoms of IBS compared to placebo over a 4-wk period.
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18
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Traini C, Faussone-Pellegrini MS, Evangelista S, Mazzaferro K, Cipriani G, Santicioli P, Vannucchi MG. Inner and outer portions of colonic circular muscle: ultrastructural and immunohistochemical changes in rat chronically treated with otilonium bromide. PLoS One 2014; 9:e103237. [PMID: 25122192 PMCID: PMC4133200 DOI: 10.1371/journal.pone.0103237] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 06/30/2014] [Indexed: 12/31/2022] Open
Abstract
Rat colonic circular muscle, main target of otilonium bromide (OB) spasmolytic activity, is subdivided in an inner and outer portion. Since the inner one is particularly rich in organelles involved in calcium availability (caveolae, smooth endoplasmic reticulum, mitochondria), the expression of specific markers (Caveolin-1, eNOS, calreticulin, calsequestrin) in comparison with the outer portion was investigated. The possible changes of these organelles and related markers, and of muscarinic receptors (Mr2) were then studied after OB chronic exposition. Rats were treated with 2-20 mg/kg/OB for 10 or 30 days. Proximal colon was processed by electron microscopy, immunohistochemistry, and western blot. In colon strips the stimulated contractility response to muscarinic agonist was investigated. The inner portion showed a higher expression of Caveolin-1 and Mr2, but not of eNOS, calreticulin and calsequestrin, compared to the outer portion. Chronic OB treatment caused similar ultrastructural and immunohistochemical changes in both portions. Organelles and some related markers were increased at 10 days; Mr2 expression and muscle contractility induced by methacholine was increased at 30 days. The present findings: 1) provide new information on the immunohistochemical properties of the inner portion of the circular layer that are in favour of a role it might play in colonic motility distinct from that of the outer portion; 2) demonstrate that chronically administered OB interferes with cell structures and molecules responsible for calcium handling and storage, and modifies cholinergic transmission. In conclusion, chronic OB administration in the colonic circular muscle layer directly interacts with the organelles and molecules calcium-related and with the Mr2.
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Affiliation(s)
- Chiara Traini
- Dept of Experimental and Clinical Medicine, Histology and Embryology Research Unit, Florence, Italy
| | | | | | - Katia Mazzaferro
- Dept of Experimental and Clinical Medicine, Histology and Embryology Research Unit, Florence, Italy
| | - Gianluca Cipriani
- Enteric Neuroscience Program, Division of Gastroenterology, Dept of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States of America
| | - Paolo Santicioli
- Dept of Experimental and Clinical Medicine, Histology and Embryology Research Unit, Florence, Italy
| | - Maria Giuliana Vannucchi
- Dept of Experimental and Clinical Medicine, Histology and Embryology Research Unit, Florence, Italy
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Vanuytsel T, Tack JF, Boeckxstaens GE. Treatment of abdominal pain in irritable bowel syndrome. J Gastroenterol 2014; 49:1193-205. [PMID: 24845149 DOI: 10.1007/s00535-014-0966-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 04/20/2014] [Indexed: 02/04/2023]
Abstract
Functional abdominal pain in the context of irritable bowel syndrome (IBS) is a challenging problem for primary care physicians, gastroenterologists and pain specialists. We review the evidence for the current and future non-pharmacological and pharmacological treatment options targeting the central nervous system and the gastrointestinal tract. Cognitive interventions such as cognitive behavioral therapy and hypnotherapy have demonstrated excellent results in IBS patients, but the limited availability and labor-intensive nature limit their routine use in daily practice. In patients who are refractory to first-line therapy, tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors are both effective to obtain symptomatic relief, but only TCAs have been shown to improve abdominal pain in meta-analyses. A diet low in fermentable carbohydrates and polyols (FODMAP) seems effective in subgroups of patients to reduce abdominal pain, bloating, and to improve the stool pattern. The evidence for fiber is limited and only isphagula may be somewhat beneficial. The efficacy of probiotics is difficult to interpret since several strains in different quantities have been used across studies. Antispasmodics, including peppermint oil, are still considered the first-line treatment for abdominal pain in IBS. Second-line therapies for diarrhea-predominant IBS include the non-absorbable antibiotic rifaximin and the 5HT3 antagonists alosetron and ramosetron, although the use of the former is restricted because of the rare risk of ischemic colitis. In laxative-resistant, constipation-predominant IBS, the chloride-secretion stimulating drugs lubiprostone and linaclotide, a guanylate cyclase C agonist that also has direct analgesic effects, reduce abdominal pain and improve the stool pattern.
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Affiliation(s)
- Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, O&N1, Box 701, Herestraat 49, 3000, Louvain, Belgium
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Rychter J, Espín F, Gallego D, Vergara P, Jiménez M, Clavé P. Colonic smooth muscle cells and colonic motility patterns as a target for irritable bowel syndrome therapy: mechanisms of action of otilonium bromide. Therap Adv Gastroenterol 2014; 7:156-66. [PMID: 25057296 PMCID: PMC4107708 DOI: 10.1177/1756283x14525250] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Otilonium bromide (OB) is a spasmolytic compound of the family of quaternary ammonium derivatives and has been successfully used in the treatment of patients with irritable bowel syndrome (IBS) due to its specific pharmacodynamic effects on motility patterns in the human colon and the contractility of colonic smooth muscle cells. This article examines how. OB inhibits the main patterns of human sigmoid motility in vitro, which are spontaneous rhythmic phasic contractions, smooth muscle tone, contractions induced by stimulation of excitatory motor neurons and contractions induced by direct effect of excitatory neurotransmitters. It does this mainly by blocking calcium influx through L-type calcium channels and interfering with mobilization of cellular calcium required for smooth muscle contraction, thereby limiting excessive intestinal contractility and abdominal cramping. OB also inhibits T-type calcium channels and muscarinic responses. Finally, OB inhibits tachykinin receptors on smooth muscle and primary afferent neurons which may have the joint effect of reducing motility and abdominal pain. All these mechanisms mediate the therapeutic effects of OB in patients with IBS and might be useful in patients with other spastic colonic motility disorders such as diverticular disease.
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Affiliation(s)
- Jakub Rychter
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - Francisco Espín
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain,Department of Surgery, Hospital de Mataró, Mataró, Spain
| | - Diana Gallego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - Patri Vergara
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain,Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marcel Jiménez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain,Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Pere Clavé
- Department of Surgery, Hospital de Mataró, Universitat Autónoma de Barcelona, C/ Cirera s/n, Mataró, Barcelona 08304, Spain
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Annaházi A, Róka R, Rosztóczy A, Wittmann T. Role of antispasmodics in the treatment of irritable bowel syndrome. World J Gastroenterol 2014; 20:6031-6043. [PMID: 24876726 PMCID: PMC4033443 DOI: 10.3748/wjg.v20.i20.6031] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 01/08/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a long-lasting, relapsing disorder characterized by abdominal pain/discomfort and altered bowel habits. Intestinal motility impairment and visceral hypersensitivity are the key factors among its multifactorial pathogenesis, both of which require effective treatment. Voltage-gated calcium channels mediate smooth muscle contraction and endocrine secretion and play important roles in neuronal transmission. Antispasmodics are a group of drugs that have been used in the treatment of IBS for decades. Alverine citrate, a spasmolytic, decreases the sensitivity of smooth muscle contractile proteins to calcium, and it is a selective 5-HT1A receptor antagonist. Alverine, in combination with simethicone, has been demonstrated to effectively reduce abdominal pain and discomfort in a large placebo-controlled trial. Mebeverine is a musculotropic agent that potently blocks intestinal peristalsis. Non-placebo-controlled trials have shown positive effects of mebeverine in IBS regarding symptom control; nevertheless, in recent placebo-controlled studies, mebeverine did not exhibit superiority over placebo. Otilonium bromide is poorly absorbed from the GI tract, where it acts locally as an L-type calcium channel blocker, an antimuscarinic and a tachykinin NK2 receptor antagonist. Otilonium has effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients. Pinaverium bromide is also an L-type calcium channel blocker that acts locally in the GI tract. Pinaverium improves motility disorders and consequently reduces stool problems in IBS patients. Phloroglucinol and trimethylphloroglucinol are non-specific antispasmodics that reduced pain in IBS patients in a placebo-controlled trial. Antispasmodics have excellent safety profiles. T-type calcium channel blockers can abolish visceral hypersensitivity in animal models, which makes them potential candidates for the development of novel therapeutic agents in the treatment of IBS.
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Triantafillidis JK, Malgarinos G. Long-term efficacy and safety of otilonium bromide in the management of irritable bowel syndrome: a literature review. Clin Exp Gastroenterol 2014; 7:75-82. [PMID: 24741324 PMCID: PMC3984067 DOI: 10.2147/ceg.s46291] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a very common functional gastrointestinal disorder characterized by abdominal pain or discomfort and altered bowel habits. The disease affects a large part of the world population. The clinical course is mostly characterized by a cyclic recurrence of symptoms. Therefore, IBS patients should receive, as an initial therapeutic approach, a short course of treatment, and long-term treatment should be reserved for those patients with recurrent symptoms. The available clinical trials show that significant improvement of the symptoms over placebo could be achieved with various drugs, although this improvement is frequently time dependent and with high relapse rates after the cessation of the treatment. In a proportion of patients, clinically obvious relapse could appear long after stopping the treatment. Some of the available pharmacologic agents, including otilonium bromide (OB), are able to significantly prolong the time to the appearance of relapse, compared with placebo. As a consequence, some authors suggest that a cyclic treatment could be of benefit. Antispasmodic drugs have been used for many years in an effort to control the symptoms of IBS. OB is a poorly absorbed spasmolytic drug, exerting significantly greater control of the symptoms of IBS compared with placebo. Recent data suggest that the drug could effectively be used for the long-term management of patients with IBS. The aim of this review is to provide the reader with an evidence-based overview of the efficacy and tolerability of OB in the long-term management of IBS patients, based on the results of the clinical trials published so far.
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Affiliation(s)
| | - George Malgarinos
- Inflammatory Bowel Disease Unit, IASO General Hospital, Athens, Greece
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Martínez-Cutillas M, Gil V, Gallego D, Mañé N, Martín MT, Jiménez M. Mechanisms of action of otilonium bromide (OB) in human cultured smooth muscle cells and rat colonic strips. Neurogastroenterol Motil 2013; 25:e803-12. [PMID: 23941257 DOI: 10.1111/nmo.12206] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 07/19/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND The pharmacological properties of otilonium bromide (OB) have been investigated using different experimental models, techniques, and conditions, and consequently, the results are not always easy to compare. The aim of the present work was to investigate the pharmacological properties of OB in human cultured colonic smooth muscle cells (HCSMCs), which is the main target of the drug 'in vivo'. Rat colonic strips were used to confirm the pharmacological properties. METHODS Human cultured colonic smooth muscle cells were studied using the calcium imaging technique. Microelectrodes and muscle bath experiments were performed in rat colonic strips. KEY RESULTS Otilonium bromide (OB) concentration dependently inhibited nifedipine-sensitive calcium transients induced by KCl (EC50 = 3.6 μM) and BayK8644 (EC50 = 4.0 μM). All the following experiments were performed in the presence of nifedipine. In HCSMC, carbachol-induced calcium transients were inhibited by OB (EC50 = 8.4 μM). Carbachol evoked 1-a smooth muscle depolarization (10 mV) that was antagonized by 100 μM OB; and 2-a contraction that was inhibited by OB (EC50 = 13.0 μM). 'Non-nitrergic (L-NNA 1 mM) non-purinergic (MRS2500 1 μM)' conditions were used to elicit endogenous excitatory responses. Electrical field stimulation caused 1-an atropine-sensitive excitatory junction potential that was inhibited by OB (EC50 = 8.9 μM) and 2-an atropine-sensitive contraction that was inhibited by OB (EC50 = 7.3 μM). In HCSMC, neurokinin A (NKA) and CaCl2 induced calcium transients that were inhibited by OB (NKA: EC50 = 11.7 μM; CaCl2 : EC50 = 17.5 μM). CONCLUSIONS & INFERENCES Otilonium bromide causes inhibition of L-/T-type calcium channels, muscarinic, and tachykininergic responses that acting together explain the pharmacological properties of the compound.
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Affiliation(s)
- M Martínez-Cutillas
- Department of Cell Biology, Physiology and Immunology and Neurosciences Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
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