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Li N, Li C, Zheng A, Liu W, Shi Y, Jiang M, Xiao Y, Qiu Z, Qiu Y, Jia A. Ultra-high-performance liquid chromatography-mass spectrometry combined with molecular docking and molecular dynamics simulation reveals the source of bitterness in the traditional Chinese medicine formula Runchang-Tongbian. Biomed Chromatogr 2024; 38:e5929. [PMID: 38881323 DOI: 10.1002/bmc.5929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 03/20/2024] [Indexed: 06/18/2024]
Abstract
The Runchang-Tongbian (RCTB) formula is a traditional Chinese medicine (TCM) formula consisting of four herbs, namely Cannabis Fructus (Huomaren), Rehmanniae Radix (Dihuang), Atractylodis Macrocephalae Rhizoma (Baizhu), and Aurantii Fructus (Zhiqiao). It is widely used clinically because of its beneficial effect on constipation. However, its strong bitter taste leads to poor patient compliance. The bitter components of TCM compounds are complex and numerous, and inhibiting the bitter taste of TCM has become a major clinical challenge. Here, we use ultra-high-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) and high-resolution mass spectrometry to identify 59 chemical components in the TCM compound RCTB formula. Next, four bitter taste receptors, TAS2R39, TAS2R14, TAS2R7, and TAS2R5, which are tightly bound to the compounds in RCTB, were screened as molecular docking receptors using the BitterX database. The top-three-scoring receptor-small-molecule complexes for each of the four receptors were selected for molecular dynamics simulation. Finally, seven bitter components were identified, namely six flavonoids (rhoifolin, naringin, poncirin, diosmin, didymin, and narirutin) and one phenylpropanoid (purpureaside C). Thus, we proposed a new method for identifying the bitter components in TCM compounds, which provides a theoretical reference for bitter taste inhibition in TCM compounds.
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Affiliation(s)
- Na Li
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Chunyu Li
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Aizhu Zheng
- The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Weipeng Liu
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Yuwen Shi
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Mengcheng Jiang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Yusheng Xiao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Zhidong Qiu
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Ye Qiu
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Ailing Jia
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
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Derayea SM, Mohammed FF, Badr El-Din KM. Sensitive spectrofluorimetric determination of the prokinetic drug prucalopride succinate based on supramolecular aggregation approach with evaluation of method greenness: application to content uniformity test. LUMINESCENCE 2023; 38:2065-2072. [PMID: 37740522 DOI: 10.1002/bio.4597] [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: 07/29/2023] [Revised: 08/24/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
The prokinetic drug, prucalopride (PCP) succinate, was determined using a new spectrofluorimetric approach with a highly sensitive, rapid, and simple procedure. The method exploited the enhancement of the inherent native fluorescence of PCP by micellar aggregation with sodium lauryl sulfate (SLS) as an anionic surfactant. Different factors that could affect the fluorescence intensity were carefully studied in order to achieve the maximal fluorescence signal. Measurement of the enhanced fluorescence was done at 354 nm after the excitation at 276 nm. The fluorescence intensity-concentration plot was rectilinear in the concentration range of 50-600 ng/ml with detection and quantitation limits of 13.9 and 42.1 ng/ml, respectively. The method underwent validation according to the International Council for Harmonisation criteria in order to assess its analytical performance, and promising results were achieved that proved the validity and reliability of the method. Furthermore, the method was employed effectively for the analysis of the cited drug in commercial pharmaceutical tablets.
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Affiliation(s)
- Sayed M Derayea
- Analytical Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Fatma F Mohammed
- Analytical Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Khalid M Badr El-Din
- Analytical Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
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Li J, Yu X, Xu X, Tang P, Bi S, Ren X, Shi Y, Wu J, Lao F. Beneficial effects of fermented jujube pulp in relieving loperamide hydrochloride-induced constipation in male ICR mice. FOOD SCIENCE AND HUMAN WELLNESS 2023. [DOI: 10.1016/j.fshw.2023.03.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
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Bassotti G, Usai Satta P, Berti G, Lai M, Villanacci V, Bellini M. Pharmacotherapeutic advances for chronic idiopathic constipation in adults. Expert Opin Pharmacother 2022; 23:2053-2078. [PMID: 36408585 DOI: 10.1080/14656566.2022.2150076] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 11/17/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Chronic idiopathic constipation is a common gastrointestinal disorder whose treatment is still far from being satisfactory for patients. Osmotic laxatives, in particular polyethylene glycol, are the first-line approach, but new emerging pharmacological agents may be useful in refractory patients. AREAS COVERED Published articles regarding the development and clinical efficacy of new agents in treating chronic idiopathic constipation were reviewed. Among emerging agents, elobixibat, a drug blocking the reabsorption of bile acids, is a promising one, especially in slow transit constipation. Linaclotide, lubiprostone and plecanatide, by a secretagogue action, improve stool consistency and increase colonic transit. Apart from prucalopride, approved in Europe for refractory chronic idiopathic constipation patients, the selective 5-HT4 agonists velusetrag and naronapride are in advanced development. In addition, relamorelin, a ghrelin agonist, seems promising for accelerating colonic transit. EXPERT OPINION Several new promising drugs have been released with the potential to be effective in the treatment of chronic idiopathic constipation. On the other hand, the experience with these new agents is still limited, especially for long-term treatment. Another important point is that these new treatments for chronic idiopathic constipation are not available worldwide and their use could be somewhat limited by their still relatively high cost.
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Affiliation(s)
- Gabrio Bassotti
- Gastroenterology, Hepatology & Digestive Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
- Gastroenterology & Hepatology Unit, Perugia General Hospital, Perugia, Italy
| | | | - Ginevra Berti
- Gastrointestina Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Mariantonia Lai
- Gastroenterology Unit, University of Cagliari, Monserrato, Italy
| | | | - Massimo Bellini
- Gastrointestina Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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Li B, Li M, Luo Y, Li R, Li W, Liu Z. Engineered 5-HT producing gut probiotic improves gastrointestinal motility and behavior disorder. Front Cell Infect Microbiol 2022; 12:1013952. [PMID: 36339343 PMCID: PMC9630942 DOI: 10.3389/fcimb.2022.1013952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/04/2022] [Indexed: 12/03/2022] Open
Abstract
Slow transit constipation is an intractable constipation with unknown aetiology and uncertain pathogenesis. The gut microbiota maintains a symbiotic relationship with the host and has an impact on host metabolism. Previous studies have reported that some gut microbes have the ability to produce 5-hydroxytryptamine (5-HT), an important neurotransmitter. However, there are scarce data exploiting the effects of gut microbiota-derived 5-HT in constipation-related disease. We genetically engineered the probiotic Escherichia coli Nissle 1917 (EcN-5-HT) for synthesizing 5-HT in situ. The ability of EcN-5-HT to secrete 5-HT in vitro and in vivo was confirmed. Then, we examined the effects of EcN-5-HT on intestinal motility in a loperamide-induced constipation mouse model. After two weeks of EcN-5-HT oral gavage, the constipation-related symptoms were relieved and gastrointestinal motility were enhanced. Meanwhile, administration of EcN-5-HT alleviated the constipation related depressive-like behaviors. We also observed improved microbiota composition during EcN-5-HT treatment. This work suggests that gut microbiota-derived 5-HT might promise a potential therapeutic strategy for constipation and related behavioral disorders.
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Affiliation(s)
- Bei Li
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
| | - Min Li
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
| | - Yanan Luo
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
| | - Rong Li
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
| | - Wei Li
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
- *Correspondence: Wei Li, ; Zhi Liu,
| | - Zhi Liu
- Department of Biotechnology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Molecular Biophysics, Ministry of Education, Wuhan, China
- *Correspondence: Wei Li, ; Zhi Liu,
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Wang Y, Xu X, Lin L. Prucalopride might improve intestinal motility by promoting the regeneration of the enteric nervous system in diabetic rats. Int J Mol Med 2022; 50:87. [PMID: 35543167 PMCID: PMC9162040 DOI: 10.3892/ijmm.2022.5143] [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: 07/21/2020] [Accepted: 05/07/2021] [Indexed: 11/14/2022] Open
Abstract
The present study aimed to investigate whether prucalopride, as a 5-hydroxytryptamine 4 (5-HT4) receptor agonist, improved intestinal motility by promoting the regeneration of the enteric nervous system (ENS) in rats with diabetes mellitus (DM). A rat model of DM was established using an intraperitoneal injection of streptozotocin. The rats were randomly divided into four groups of 6 rats/group: Control, DM (DM model), DM + A (5 µg/kg prucalopride) and DM + B (10 µg/kg prucalopride). The rats in the Control group were given an equal volume of citric acid solvent. After successful model establishment, high blood glucose levels were maintained for 2 weeks before administration of prucalopride. The colonic transit time was measured using the glass bead discharge method. It was revealed that the colonic transit time of diabetic rats was the longest, and this was significantly shortened in the DM + B group. Subsequently, the colons were collected. The expression levels of Nestin, glial fibrillary acidic protein (GFAP), SOX10, RNA-binding protein human antigen D (HuD) and ubiquitin thiolesterase (PGP9.5) were determined via immunohistochemical analysis. Immunofluorescence double staining of 5-HT4 + Nestin and Ki67 + Nestin was performed. The 5-HT level was measured using ELISA. Compared with that in the control group, Nestin expression was significantly increased in the DM and DM + A groups, and it was concentrated in columnar epithelial cells and the mesenchyme. Furthermore, the expression levels of Nestin in the DM + A group were higher than those in the DM group. No difference was observed in the expression levels of Nestin between the DM + B group and the Control group. The expression levels of 5-HT protein were highest in the Control group; however, the expression levels of 5-HT protein in the DM group, DM + A group and DM + B group exhibited an increasing trend. Similar trends in the expression of 5-HT4 and Nestin were not observed; however, similar trends in the expression of Nestin and Ki67 were observed. The expression levels of GFAP, SOX10, PGP9.5 and Ki67 in the DM + A and DM + B groups were higher compared with those in the DM group. In the DM + A group, HuD expression was decreased compared with that in the Control group but it was markedly higher compared with that in the DM group. In conclusion, prucalopride may improve intestinal motility by promoting ENS regeneration in rats with DM.
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Affiliation(s)
- Yun Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xinyu Xu
- Department of Spleen and Stomach Disease, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, Jiangsu 210014, P.R. China
| | - Lin Lin
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Hong JT. Current Opinion on Prucalopride in Gastroparesis and Chronic Constipation Treatment: A Focus on Patient Selection and Safety. Ther Clin Risk Manag 2021; 17:601-615. [PMID: 34135588 PMCID: PMC8197617 DOI: 10.2147/tcrm.s269330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022] Open
Abstract
Prucalopride is a third-generation, highly selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist. Many recent studies indicate prucalopride may play an important role in various motility disorders. The aim of this study was to investigate safety and patient selection considerations when using prucalopride as gastroparesis and chronic constipation treatment. We systematically searched PubMed, Embase, the Cochrane Central Register and ClinicalTrials.gov, and we reviewed all studies that evaluated prucalopride for the treatment of gastroparesis and chronic idiopathic constipation in adults. Prucalopride is an effective and safe option based on all the studies currently conducted. Thus, it may be the first-line treatment in the future. Prucalopride has the potential to be useful in the treatment of functional constipation and other forms of gastrointestinal diseases (eg, gastroparesis). Through the research on this potential, prucalopride is expected to be a useful and versatile option for treating gastrointestinal diseases in the future.
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Affiliation(s)
- Ji Taek Hong
- Division of Gastroenterology, Department of Medicine, Ewha Womans University College of Medicine, Seoul, Korea
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Du D, Wu H. Synthesis and crystal structure of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[ b][1,4]thiazepin-4(5 H)-one. JOURNAL OF CHEMICAL RESEARCH 2020. [DOI: 10.1177/1747519820907877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
7-Bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[ b][1,4]thiazepin-4(5 H)-one is prepared from 6-methoxybenzo[ d]thiazol-2-amine and 2-(bromomethyl)-2-butylhexanoic acid as the key starting materials via five simple steps including hydrolysis, substitution, condensation, bromination, and aromatic amidation under microwave conditions. This new route has reduced the reaction time and increased the overall yield to 43%. Moreover, the structure of the target product is also confirmed by X-ray crystal analysis, and further studies indicate that the existence of an intramolecular C–H···C g1 non-classical hydrogen bond is effective in stabilization of the crystal structure.
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Affiliation(s)
- Damin Du
- Department of Physics, Taizhou University, Taizhou, P.R. of China
| | - Haijian Wu
- Advanced Research Institute and Department of Chemistry, Taizhou University, Taizhou, P.R. of China
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Bassotti G, Usai Satta P, Bellini M. Plecanatide for the treatment of chronic idiopathic constipation in adult patients. Expert Rev Clin Pharmacol 2019; 12:1019-1026. [PMID: 31575291 DOI: 10.1080/17512433.2019.1670057] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 09/17/2019] [Indexed: 12/14/2022]
Abstract
Introduction. Chronic idiopathic constipation (CIC) is a functional gastrointestinal disorder that is associated with an increased healthcare cost and an abnormally poor quality of life. Plecanatide is a natural analog to the peptide agonist of the guanylate cyclase-C (GC-C) receptor, uroguanylin. The conversion of guanosine 5-triphosphate to cyclic guanosine monophosphate results in an increased bowel fluid secretion. Plecanatide is a promising new agent for CIC unresponsive to current therapeutic regimes.Areas covered. A comprehensive online search of Medline and the Science Citation Index was made using the keywords 'plecanatide', 'guanylate cyclase-C agonists', and 'constipation', in various combinations. We reviewed the pharmacodynamics, pharmacokinetics, and metabolism of this agent, and the most significant studies regarding the clinical efficacy and safety of plecanatide in CIC therapy.Expert opinion. Experimental studies showed that plecanatide was significantly better than placebo in reducing CIC severity, straining, stool consistency, bowel movements and quality of life. Apart from limited cases of diarrhea, no serious adverse events were reported. However, few data are available on its long-term safety. Furthermore, patients' affordability of plecanatide can be limited by its costs. Finally, this new agent with a different way of action can be proposed in patients refractory to common therapy.
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Affiliation(s)
- Gabrio Bassotti
- Gastroenterology & Hepatology Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy
| | | | - Massimo Bellini
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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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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Kim JE, Lee YJ, Ryu SH, Park JW, Kang MJ, Choi HJ, Bae SJ, Choi Y, Kang HG, Kim KB, Kim S, Lim Y, Hwang DY. Metabolomics approach to serum biomarker for laxative effects of red Liriope platyphylla in loperamide-induced constipation of SD rats. Lab Anim Res 2019; 35:9. [PMID: 32257897 PMCID: PMC7081617 DOI: 10.1186/s42826-019-0009-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 07/04/2019] [Indexed: 02/07/2023] Open
Abstract
Red Liriope platyphylla (RLP) is a known herbal medicine used in the treatment of some chronic diseases including constipation, neurodegenerative disorders, diabetes and obesity. To determine and characterize putative biomarkers that predict the laxative effects induced by RLP treatment, alteration of endogenous metabolites was measured in the serum of loperamide (Lop)-induced constipation rats after administration of RLP extract (EtRLP) using 1H nuclear magnetic resonance (1H NMR) spectral data. The urine volume and amounts, and weights and water contents of stools were significantly recovered in the Lop + EtRLP treated group as compared to the No group, whereas body weight and food intake maintained constant levels. Also, significant recoveries in the thickness of mucosa and muscle were detected in the colon of the Lop + EtRLP treated group. Furthermore, pattern recognition showed absolutely different clustering of the serum analysis parameters when comparing the Lop treated group and Lop + EtRLP treated group. Of the 33 endogenous metabolites, 7 amino acids (alanine, arginine, glutamate, glutamine, glycine, threonine and valine) and 8 endogenous metabolites (betaine, creatine, glucose, taurine, ethanol, lactate, glycerol and succinate) were dramatically increased in the Lop + EtRLP treated SD rats. These results provide the first evidence pertaining to metabolic changes in the constipation rats treated with Lop + EtRLP. Additionally, these findings correlate with changes observed in 15 metabolites during the laxative effects of EtRLP.
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Affiliation(s)
- Ji Eun Kim
- 1Department of Biomaterials Science, College of Natural Resources & Life Science / Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do 627-706 South Korea
| | - Young Ju Lee
- 1Department of Biomaterials Science, College of Natural Resources & Life Science / Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do 627-706 South Korea
| | - Sung Ha Ryu
- Analysis Research Team, R&D Center, GL Pharm Tech Corp, Gyeonggi-do, 13202 Republic of Korea.,4College of Pharmacy, Dankook University, Chungnam, 330-714 South Korea
| | - Ji Won Park
- 1Department of Biomaterials Science, College of Natural Resources & Life Science / Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do 627-706 South Korea
| | - Mi Ju Kang
- 1Department of Biomaterials Science, College of Natural Resources & Life Science / Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do 627-706 South Korea
| | - Hyeon Jun Choi
- 1Department of Biomaterials Science, College of Natural Resources & Life Science / Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do 627-706 South Korea
| | - Su Ji Bae
- 1Department of Biomaterials Science, College of Natural Resources & Life Science / Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do 627-706 South Korea
| | - Yusang Choi
- 1Department of Biomaterials Science, College of Natural Resources & Life Science / Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do 627-706 South Korea
| | - Hyun Gu Kang
- 3Laboratory of Veterinary Theriogenology, Department of Veterinary Medicine, College of Veterinary Medicine, Chungbuk National University, Cheongju, 28644 South Korea
| | - Kyu-Bong Kim
- 4College of Pharmacy, Dankook University, Chungnam, 330-714 South Korea
| | - Suhkmann Kim
- 5Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan, 609-735 South Korea
| | - Yong Lim
- 6Department of Clinical Laboratory Science, College of Nursing and Healthcare Science, Dong-Eui University, Busan, South Korea
| | - Dae Youn Hwang
- 1Department of Biomaterials Science, College of Natural Resources & Life Science / Industry Convergence Research Institute, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup Miryang-si, Gyeongsangnam-do 627-706 South Korea
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Bassotti G, Usai Satta P, Bellini M. Prucalopride for the treatment of constipation: a view from 2015 and beyond. Expert Rev Gastroenterol Hepatol 2019; 13:257-262. [PMID: 30791758 DOI: 10.1080/17474124.2019.1568238] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 01/07/2019] [Indexed: 12/19/2022]
Abstract
Prucalopride is a prokinetic drug, that has been commercially available in recent years for the treatment of chronically constipated patients. In this update of a previous 2016 article, we reviewed the more recent data supporting its role in the treatment of constipation and constipation-associated conditions. Areas covered: We carried out an extensive literature review on the effects of prucalopride for the years 2012-2018 by means of scientific databases and manual research. More evidence was found on its possible therapeutic role in conditions in which constipation plays a role as an associated symptom, such as opioid-induced constipation, constipation-predominant irritable bowel syndrome, post-operative ileus, colonic diverticular disease, drug-related constipation, and chronic intestinal pseudo-obstruction. Expert opinion: Based on the added literature evidence, we feel that prucalopride is an effective, although expensive, drug for the treatment of primary and secondary forms of constipation, and of other clinical conditions associated with constipation.
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Affiliation(s)
- Gabrio Bassotti
- a Gastroenterology & Hepatology Section, Department of Medicine , University of Perugia Medical School , Perugia , Italy
| | - Paolo Usai Satta
- b Gastrointestinal Unit , "G. Brotzu" Hospital , Cagliari , Italy
| | - Massimo Bellini
- c Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery , University of Pisa , Pisa , Italy
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Yue Y, Wang X, Yang H, Sun M, Chen S, Qian H, Xu T, Yan S. Clinical efficacy of the traditional Chinese herbal formula, (Tong Bian Decoction) on laxative dependence constipation in elderly persons: A randomized, multicenter, controlled trial. Eur J Integr Med 2018. [DOI: 10.1016/j.eujim.2018.10.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Battaglia E, Grassini M, Dore MP, Bassotti G. Usefulness of Bisacodyl Testing on Therapeutic Outcomes in Refractory Constipation. Dig Dis Sci 2018; 63:3105-3111. [PMID: 29484568 DOI: 10.1007/s10620-018-4988-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 02/18/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Although chronically constipated patients usually respond to medical treatment, there is a subgroup with scarce/no response, generally labeled as refractory or intractable. However, whether this lack of response is real or due to ancillary causes (suboptimal dosage, lack of compliance etc.) is unknown. AIMS To see whether a pharmacologic test (bisacodyl colonic intraluminal infusion during manometric assessment) may predict the therapeutic outcome. METHODS Data of patients undergoing 24/h colonic manometry for severe intractable constipation in whom the bisacodyl test (10 ml of drug dissolved into saline and injected through the more proximal recording port) had been carried out were retrieved and analysed, and correlations with the therapeutic outcome made. RESULTS Overall, charts from 38 patients (5 men) were available; of these, only 21% displayed naive high-amplitude propagated contractions (average, less than 2/24 h), mostly meal-induced, during the recordings. A bisacodyl response was present in 31.6% patients, with a mean number of events of 1.8 per patient. After bisacodyl testing, 47.3% patients underwent intensive medical treatment, 44.7% surgery (medical failures), and 8% transanal irrigation, a procedure employed to treat refractory patients. The presence of naive propulsive contractions significantly correlated with the response to bisacodyl infusion (p < 0.0001), and with a favourable outcome to intensive medical treatment (p < 0.0001). CONCLUSIONS The bisacodyl test may be clinically useful to better categorize constipated patients erroneously labelled as intractable and to exclude true colonic inertia, thus avoiding surgery in more than 30% of these subjects.
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Affiliation(s)
- Edda Battaglia
- Gastroenterology and Endoscopy Unit, Cardinal Massaja Hospital, Asti, Italy
| | - Mario Grassini
- Gastroenterology and Endoscopy Unit, Cardinal Massaja Hospital, Asti, Italy
| | - Maria Pina Dore
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia School of Medicine, Perugia, Italy.
- Clinica di Gastroenterologia, Ospedale Santa Maria della Misericordia, Piazzale Menghini 1, 06156, San Sisto, Perugia, Italy.
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Zhang Y, Ge T, Xiang P, Mao H, Tang S, Li A, Lin L, Wei Y. Therapeutic effect of protease-activated receptor 2 agonist SLIGRL-NH 2 on loperamide-induced Sprague-Dawley rat constipation model and the related mechanism. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:2403-2411. [PMID: 30122898 PMCID: PMC6078190 DOI: 10.2147/dddt.s160628] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Purpose To investigate the therapeutic effects of protease-activated receptor 2 (PAR-2) agonist SLIGRL-NH2 on loperamide-induced Sprague-Dawley (SD) rat constipation animal models. Materials and methods Loperamide was injected subcutaneously to induce constipation twice a day for 3 days. SD rats (n = 30) were randomly divided into five groups: non-constipation group (control, n = 6), constipation group (constipation, n = 6), constipation + SLIGRL-NH2 low-dosage group (SLIGRL-NH2 low, n=6), constipation + SLIGRL-NH2 high-dosage group (SLIGRL-NH2 high, n = 6), and constipation + prucalopride (positive control, n = 6). The SLIGRL-NH2 low group and SLIGRL-NH2 high group were administered with 2.5 μmol/kg and 5 μmol/kg SLIGRL-NH2, respectively, and the prucalopride group received 2 mg/kg prucalopride. The control and constipation group received 1× PBS under the same pattern. SLIGRL-NH2 and prucalopride were orally administrated once daily for 7 days. On the final day of oral administration, food intake, water intake, the number of stool pellets, weight, and fecal water content was calculated; moreover, the colons of rats in different groups were collected and histological features were examined by hematoxylin and eosin staining; furthermore, the expression of anoctamin-1 was determined by Immunohistochemical methods, and the expressions of c-kit and PAR-2 were examined using real-time quantitative polymerase chain reaction and Western blot methods; finally, the expressions of neurotransmitter vasoactive intestinal peptide (VIP) and substance P (SP) were examined using enzyme-linked immuno-sorbent assay methods. Results The feeding and excretion behaviors, intestinal transit ratio, and the histological feature of the colon in the constipated rats were all improved by SLIGRL-NH2 treatment; moreover, SLIGRL-NH2 treatment induced significant increase in the expression of PAR-2 and also increased number of interstitial Cajal cells. Furthermore, SLIGRL-NH2 also decreased the contents of the inhibitory neurotransmitter VIP and increased the expression of the excitatory neurotransmitter SP. High dose of SLIGRL-NH2 has shown similar anti-constipation effects as prucalopride. Conclusion These results suggested that SLIGRL-NH2 can enhance gastrointestinal transit and alleviate in rats with loperamide-induced constipation.
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Affiliation(s)
- Yonggang Zhang
- Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China
| | - Tingrui Ge
- Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China
| | - Ping Xiang
- Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China
| | - Haibing Mao
- Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China
| | - Shumin Tang
- Department of Colorectal Surgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China
| | - Aimin Li
- Department of Neurosurgery, The First People's Hospital of Lianyungang, Lianyungang 222002, China
| | - Lin Lin
- Department of Gastroenterology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yinting Wei
- Department of Gastroenterology, Lianyungang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Lianyungang 222000, China,
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16
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Bacterial overgrowth, dysbiosis, inflammation, and dysmotility in the Cystic Fibrosis intestine. J Cyst Fibros 2018; 16 Suppl 2:S14-S23. [PMID: 28986022 DOI: 10.1016/j.jcf.2017.07.014] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 07/15/2017] [Accepted: 07/17/2017] [Indexed: 02/08/2023]
Abstract
Gastrointestinal disease in Cystic Fibrosis (CF) is caused by defective chloride and bicarbonate transport in intestinal cells leading to reduced intraluminal fluidity, increased mucous viscosity and consequently development of intestinal inflammation, dysbiosis and often times dysmotility. This triad is also referred to as the "CF gut". A diagnosis is mainly based on clinical observation and treatment is often times decided empirically. This review of the literature should provide CF caregivers with some tools to identify intestinal inflammation, dysbiosis and dysmotility as possible cause for their patient's gastrointestinal complaints and provide an overview of our current approach to its management.
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Zheng S, Yao J, the Chinese Geriatric Society, Editorial Board of Chinese Journal of Geriatrics. Expert consensus on the assessment and treatment of chronic constipation in the elderly. Aging Med (Milton) 2018; 1:8-17. [PMID: 31942474 PMCID: PMC6880707 DOI: 10.1002/agm2.12013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 03/07/2018] [Indexed: 12/11/2022] Open
Abstract
It is of significant importance to scientifically assess and efficiently address chronic constipation in the elderly population. Therefore, organizing some domestic experts of geriatrics and gastroenterology, we have formulated this consensus to reference for clinical staff.
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Corleto VD, Antonelli G, Coluccio C, D’Alba L, di Giulio E. Efficacy of Prucalopride in bowel cleansing before colonoscopy: Results of a pilot study. World J Gastrointest Endosc 2017; 9:558-560. [PMID: 29184612 PMCID: PMC5696608 DOI: 10.4253/wjge.v9.i11.558] [Citation(s) in RCA: 7] [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] [Received: 06/09/2017] [Revised: 07/11/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
Colonoscopy is a crucial diagnostic instrument for colorectal cancer screening and an adequate bowel preparation is definitely decisive for the success of the procedure. Especially in elderly patients, bowel cleansing is considered a big issue, because it is often poorly tolerated for many reasons (like inability to swallow large volume of liquids or unlikable taste); this can cause a suboptimal preparation that may lead to miss a neoplastic lesion. There is relatively little data about how to improve preparation tolerability. The purpose of our pilot study was to analyze the effect of prucalopride (Resolor®), a highly selective serotonin 5HT4 receptor agonist used for chronic constipation for its ability to stimulate gastrointestinal peristalsis, undertaken the day before colonoscopy, followed by half volume of polyethylene glycol solution. We found that this can be a good and safe method to achieve an adequate and better-tolerated colon cleansing.
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Affiliation(s)
- Vito Domenico Corleto
- Department of Digestive Endoscopy, School of Medicine and Psychology, “Sapienza” University of Rome, Sant’Andrea Hospital, 00189 Rome, Italy
| | - Giulio Antonelli
- Department of Digestive Endoscopy, School of Medicine and Psychology, “Sapienza” University of Rome, Sant’Andrea Hospital, 00189 Rome, Italy
| | - Chiara Coluccio
- Department of Digestive Endoscopy, School of Medicine and Psychology, “Sapienza” University of Rome, Sant’Andrea Hospital, 00189 Rome, Italy
| | - Lucia D’Alba
- Gastroenterology and Digestive Endoscopy, San Giovanni-Addolorata Hospital, 00184 Rome, Italy
| | - Emilio di Giulio
- Department of Digestive Endoscopy, School of Medicine and Psychology, “Sapienza” University of Rome, Sant’Andrea Hospital, 00189 Rome, Italy
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Laus F, Fratini M, Paggi E, Faillace V, Spaterna A, Tesei B, Fettucciari K, Bassotti G. Effects of Single-Dose Prucalopride on Intestinal Hypomotility in Horses: Preliminary Observations. Sci Rep 2017; 7:41526. [PMID: 28128322 PMCID: PMC5269739 DOI: 10.1038/srep41526] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 12/21/2016] [Indexed: 11/08/2022] Open
Abstract
Abnormalities of gastrointestinal motility are often a challenge in horses; however, the use of prokinetic drugs in such conditions must be firmly established yet. For this reason we carried out a preliminary study on the effects of prucalopride on intestinal motor activity of horses with gut hypomotility. The effect of prucalopride per os by oral dose syringe (2 mg/100 kg body weight) was assessed by abdominal ultrasound (evaluating duodenal, cecal, and colonic motor activity) in six horses with gut hypomotility. After administration of prucalopride, a significant increase of contractile activity was found in the duodenum at 30 minutes (p = 0.0005), 60 minutes (p = 0.01) and 90 minutes (p = 0.01), whereas in the cecum and in the left colon the increase was only present at 60 minutes (p = 0.03, and p = 0.02, respectively). No changes from baseline heart and respiratory rate or behavior side effects were observed after administration of the drug and throughout the observation period. Prucalopride may be a useful adjunct to the therapeutic armamentary for treating hypomotile upper gut conditions of horses. Dosing information is however needed to establish its actual clinical efficacy and its proper effects on the large bowel in these animals.
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Affiliation(s)
- Fulvio Laus
- School of Bioscences and Veterinary Medicine, University of Camerino, Via Circonvallazione 63/95, 62024 Matelica, Italy
| | - Margherita Fratini
- School of Bioscences and Veterinary Medicine, University of Camerino, Via Circonvallazione 63/95, 62024 Matelica, Italy
| | - Emanuele Paggi
- School of Bioscences and Veterinary Medicine, University of Camerino, Via Circonvallazione 63/95, 62024 Matelica, Italy
| | - Vanessa Faillace
- School of Bioscences and Veterinary Medicine, University of Camerino, Via Circonvallazione 63/95, 62024 Matelica, Italy
| | - Andrea Spaterna
- School of Bioscences and Veterinary Medicine, University of Camerino, Via Circonvallazione 63/95, 62024 Matelica, Italy
| | - Beniamino Tesei
- School of Bioscences and Veterinary Medicine, University of Camerino, Via Circonvallazione 63/95, 62024 Matelica, Italy
| | - Katia Fettucciari
- Department of Experimental Medicine, Perugia University School of Medicine, Piazzale Lucio Severi, 1, 06159 San Sisto (Perugia), Italy
| | - Gabrio Bassotti
- Department of Medicine, Perugia University School of Medicine, Piazzale Lucio Severi, 1, 06159 San Sisto (Perugia), Italy
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Pharmacokinetics and tissue distribution study of prucalopride in rats by ultra high performance liquid chromatography with tandem mass spectrometry. J Pharm Biomed Anal 2016; 131:246-255. [PMID: 27611096 DOI: 10.1016/j.jpba.2016.08.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/12/2016] [Accepted: 08/27/2016] [Indexed: 02/08/2023]
Abstract
A sensitive, reliable and high throughput ultra high performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of prucalopride in rat plasma and various tissues (including heart, liver, spleen, lung, kidney, stomach,small intestine, large intestine, cecum, cerebrum, cerebellum, and ovary). The plasma and tissues samples were treated by protein precipitation with acetonitrile using carbamazepine as an internal standard (IS). Chromatographic separation was performed on a Waters ACQUITY UPLC® HSS C18 column (2.1mm×50mm, 1.8μm) with a gradient mobile phase consisting of acetonitrile-water (containing 0.1% formic acid) as mobile phase at a flow rate of 0.2mL/min. The quantification was performed by multiple reactions monitoring mode with m/z 367.99→195.89 for prucalopride and m/z 236.97→194.04 for carbamazepine on a Waters Xevo TQD mass spectrometry equipped with electrospray ionization (ESI) source. The calibration curve was linear in the range of 0.1-100ng/mL for plasma and various tissues (r≥0.99) with a lower limit of quantification of 0.1ng/mL. The recoveries obtained for prucalopride were more than 85%. The validated method was successfully applied to the pharmacokinetics and tissue distribution study of prucalopride after oral administration to rats. The pharmacokinetic parameters were demonstrated as followed: the time to reach peak concentration (Tmax) was 1.0h, and the peak concentration (Cmax) was 21.71±4.28ng/mL, the half-life (t1/2) was 18.21±0.69h, and the area under the curve (AUC) was 59.30±9.43ngh/mL. Tissue distribution showed the highest level was observed in stomach and intestine, then in liver, which indicated that prucalopride was absorbed firstly in stomach and intestine, and mainly accumulated in liver. It was also the first study to investigate the tissue distribution of prucalopride in rats following oral administration.
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Abstract
INTRODUCTION Chronic constipation is a frequent complaint in daily clinical practice. Notwithstanding the availability of numerous drugs, its treatment it is still unsatisfactory. However, new emerging treatments are in the pipeline and some drugs seem to be promising; among these velusetrag, a selective 5-HT4 receptors agonist. AREAS COVERED An in depth Medline literature search was performed concerning topics related to the treatment of constipated patients with velusetrag. In addition, abstracts concerning the topic were searched by hand in our libraries. EXPERT OPINION After analyzing the available data, the authors feel that velusetrag may likely improve symptoms and the quality of life of chronically constipated subjects. However, additional data is needed to fully understand the safety and efficacy of velusetrag, particularly in patients on long-term therapy. Thanks to the once-daily dosing and the pharmacologic properties, velusetrag could be used as a single agent or in association with other drugs. In the future, this drug holds the potential to be an effective adjunct to the therapeutic armamentarium for chronic constipation.
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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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Bellini M, Gambaccini D, Bassotti G. Prucalopride: For functional constipation only? Tech Coloproctol 2016; 20:433-436. [PMID: 27174045 DOI: 10.1007/s10151-016-1477-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 04/29/2016] [Indexed: 01/25/2023]
Abstract
Prucalopride is a new prokinetic agent, recently available in Europe for the treatment of functional constipation in adults in whom treatment with laxatives failed to provide adequate relief. However, due to its intrinsic properties (highly selective agonist activity and high affinity for 5-HT4 receptors, neuroprotection), this drug has shown the potential to be used in other pathologic conditions, in and outside of the gastrointestinal tract. We performed a systematic review of the evidence supporting these possible alternative uses of prucalopride. Further studies in this area are, however, mandatory.
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Affiliation(s)
- M Bellini
- Gastrointestinal Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy
| | - D Gambaccini
- Gastrointestinal Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy
| | - G Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia Medical School, Piazza Lucio Severi, 1, 06132, San Sisto (Perugia), Italy.
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