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Gao P, Wang L, Chen Y, Yang X, Chen X, Yue C, Wu T, Jiang T, Wu H, Tang L, Wang Z. Pharbitidis Semen: A review of botany, traditional uses, phytochemistry, pharmacology, and toxicology. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116634. [PMID: 37178984 DOI: 10.1016/j.jep.2023.116634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/17/2023] [Accepted: 05/11/2023] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pharbitidis Semen (the seeds of Ipomoea nil (L.) Roth or Ipomoea purpurea (L.) Roth), a popular traditional Chinese medicine, is also known as "Heichou" or "Baichou" (Chinese: , ). It can purge the bowels, promote diuresis, remove stagnated accumulation, and kill worms. It can be used for treating anasarca with constipation and oliguria; dyspnea and cough caused by retained fluid; abdominal pain because of intestinal parasitosis; ascariasis; and taeniasis. AIMS This review discusses the botany, ethnopharmacology, phytochemistry, pharmacological activities, toxicology, and quality control of Pharbitidis Semen, to obtain a complete understanding of its effects and provide a basis for further research and the development of new drugs. MATERIALS AND METHODS The literature on Pharbitidis Semen is mainly obtained from pharmacopoeias of different countries, masterpieces of traditional Chinese medicine, Master's and Ph.D. theses, and published articles obtained from literature retrieval websites, such as CNKI, PubMed, SciFinder, WanFang data, Web of Science, Springer, ScienceDirect, Wiley, ACS Publications, Taylor & Francis, J-STAGE, and Google Scholar. Its botany, ethnopharmacology, phytochemistry, pharmacological activities, toxicology, and quality control are discussed to understand its effects and provide a basis for further research. RESULTS Pharbitidis semen has been used ethnomedically in many tropical and subtropical countries as deobstruents, diuretics, and anthelmintics. About 170 chemical compounds, including terpenoids, phenylpropanoids, resin glycosides, fatty acids and other compounds, have been isolated. It has been reported to have different effects, including laxative, renal-protective, neuroprotective, insecticidal, antitumor, anti-inflammatory, and antioxidant. Moreover, a brief introduction to processing, toxicity, and quality control is provided. CONCLUSIONS The traditional efficacy of Pharbitidis Semen in diarrhea has been confirmed, but its bioactive and toxic ingredients are not entirely clear. It is necessary to strengthen the research and identification of effective parts or natural active components of Pharbitidis Semen, clarify the molecular mechanism of its toxicity and change rule of endogenous substances to make Pharbitidis Semen better used in clinical practice. Additionally, the imperfect quality standard is also a challenge that must be solved urgently. The study of modern pharmacology has broadened the application of Pharbitidis Semen and provided ideas for better utilization of this resource.
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Affiliation(s)
- Peiyun Gao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China; College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, China
| | - Lixia Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Yingying Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xiaoyun Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xiaoxu Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Chunyu Yue
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China; College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, China
| | - Tong Wu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Tong Jiang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Hongwei Wu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Liying Tang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Zhuju Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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Lee JY, Kim N, Yoon H, Shin CM, Park YS, Lee DH. A Randomized, Double-Blinded, Placebo-controlled Study to Evaluate the Efficacy and Safety of DA-9701 (Motilitone) in Patients With Functional Dyspepsia and Constipation-type Irritable Bowel Syndrome Overlap: A Pilot Study. J Neurogastroenterol Motil 2022; 28:265-275. [PMID: 35232894 PMCID: PMC8978125 DOI: 10.5056/jnm20236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 03/30/2021] [Accepted: 05/17/2021] [Indexed: 11/20/2022] Open
Abstract
Background/Aims To assess the effects and safety of DA-9701 in patients with constipation-type irritable bowel syndrome (IBS-C) which frequently accompany functional dyspepsia (FD). Methods FD and IBS-C were diagnosed based on the Rome III criteria. Randomized subjects were administered 30 mg of DA-9701 (Motilitone) or placebo 3 times a day for 4 weeks. The study endpoints were evaluated the percentage of responders in the overall symptom evaluation of IBS-C and FD. Results Thirty IBS-C patients and 30 placebos were prospectively enrolled. The proportion of responders with improvement in overall symptoms of IBS-C was 53.33% in the DA-9701 group and 40.00% in the placebo group (P = 0.301). Compared to the placebo group, the decrease of abdominal pain score in the DA-9701 group was significantly higher at week 3 in the DA-9701 group (0.96 ± 0.77 vs 0.55 ± 0.79, P = 0.042) but no significance at week 4. There was no significant difference in total IBS quality of life score at week 4 between the 2 groups (P = 0.897). Among patients with IBS-C accompanied by FD, the proportion of responders in the DA-9701 group was 50.00% (15/30), which was higher than 31.03% (9/29) of the placebo group (P = 0.138). Conclusions DA-9701 showed trend of treatment efficacy in patients with FD and IBS-C overlap including overall improvement, and safety, compared to placebo but without significance probably due to small numbers. It is suggested the need for a large-scale clinical trial to confirm this preliminary effect of DA-9701.
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Affiliation(s)
- Ju Yup Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, South Korea.,Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, South Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, South Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, South Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
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Effect of DA-9701 on the Gastrointestinal Motility in the Streptozotocin-Induced Diabetic Mice. J Clin Med 2021; 10:jcm10225282. [PMID: 34830563 PMCID: PMC8623860 DOI: 10.3390/jcm10225282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Compared to the general population, diabetic patients experience more frequent episodes of gastrointestinal (GI) motility dysfunction, owing to the disruption of functional innervations. DA-9701 is a new prokinetic agent formulated from the extracts of Pharbitidis semen and Corydalis tuber. Aim: To investigate the effect of DA-9701 on GI motility in an animal model of streptozotocin (STZ)-induced diabetes. Methods: Diabetes was induced in mice by intraperitoneal injection of STZ (40 mg/kg of body weight in 0.1 M citrate buffer) for 3 days. Diabetic mice were divided into four groups and administered DA-9701 in different doses (1, 3, and 10 mg/kg) or placebo for 2 weeks. Intestinal transit was assessed using charcoal meal movement. GI isometric contraction was measured by applying an isometric force transducer on a circular muscle strip of the antrum, ileum, and proximal colon of sacrificed mice. Gastric emptying rate was evaluated by measuring the dye percentage remaining in the stomach relative to the total dye amount recovered in a standardization group of mice. Results: Body weight and antral and small intestinal motility were less in diabetic mice than in control mice, and colonic motility was similar in both. DA-9701 showed a dose-dependent increase in the amplitude of spontaneous phasic contractions in the antrum, ileum, and colon in diabetic mice without influencing body weight or blood glucose levels. The degree of improvement was comparable between diabetic and control mice. Intestinal transit was significantly more delayed in diabetic mice than in controls (43 ± 7% vs. 67 ± 8%, p < 0.05); however, DA-9701 restored the delayed intestinal transit more effectively compared to placebo (75% vs. 50%). The gastric emptying rate was significantly more delayed in diabetic mice than in controls (43 ± 10% vs. 62 ± 12%, p < 0.05), and was improved by DA-9701 in a dose-dependent manner (50%, 55%, and 60% in mice treated with 1, 3, and 10 mg/kg of DA-9701, respectively, vs. 43% in placebo-treated and 60% in control mice). Conclusions: DA-9701 improved GI contractility without affecting blood sugar and body weight in diabetic mice. DA-9701 could improve the decreased GI motility and clinical symptoms in progressive diabetic patients.
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Choi J, Lee J, Cho JW, Koh S, Yang YS, Yoo D, Shin C, Kim HT. Double-Blind, Randomized, Placebo-Controlled Trial of DA-9701 in Parkinson's Disease: PASS-GI Study. Mov Disord 2020; 35:1966-1976. [PMID: 32761955 PMCID: PMC7754502 DOI: 10.1002/mds.28219] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/17/2020] [Accepted: 06/24/2020] [Indexed: 01/12/2023] Open
Abstract
OBJECTIVES This study aimed to assess the efficacy of DA-9701 on gastrointestinal symptom-related quality of life in patients with Parkinson's disease on stable dopaminergic medications. METHODS This multicenter, double-blind, placebo-controlled, phase 4 trial included a total of 144 patients with Parkinson's disease with gastrointestinal dysfunctions based on predefined criteria. Participants were randomized to take either DA-9701 or placebo for 4 weeks, and then both groups were administered DA-9701 for an additional 8 weeks while antiparkinsonian medications were unchanged. The primary outcome measure was gastrointestinal symptoms and related quality-of-life changes assessed on the Korean Nepean dyspepsia index after 4 and 12 weeks of therapy. We also evaluated the impact of DA-9701 therapy on parkinsonian motor symptoms at each time point. RESULTS The gastrointestinal symptom-related quality-of-life score significantly improved in the DA-9701-treated group compared with the placebo-treated group after 4weeks (adjusted P = 0.012 by linear mixed effect model analysis). The overall gastrointestinal symptom and dyspepsia sum scores improved at 12 weeks after intervention in the DA-9701-first treated group (adjusted P = 0.002 and 0.014, respectively) and also in the placebo-first treated group (adjusted P = 0.019 and 0.039) compared with the baseline. Parkinsonian motor severity was not significantly affected by DA-9701 treatment in both groups at 4 and 12 weeks after intervention. There were no drug-related serious adverse events throughout the trial. CONCLUSIONS DA-9701 therapy improved gastrointestinal symptom-related quality of life, and 12 weeks of daily administration can relieve the overall severity of gastrointestinal symptoms in patients with Parkinson's disease without affecting motor symptoms. (Clinical trial identifier: NCT02775591.) © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Ji‐Hyun Choi
- Department of Neurology, Seoul Metropolitan Government‐Seoul National University Boramae Medical CenterSeoul National University College of MedicineSeoulSouth Korea
| | - Jee‐Young Lee
- Department of Neurology, Seoul Metropolitan Government‐Seoul National University Boramae Medical CenterSeoul National University College of MedicineSeoulSouth Korea
| | - Jin Whan Cho
- Department of Neurology, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
| | - Seong‐Beom Koh
- Department of NeurologyKorea University Guro HospitalSeoulSouth Korea
| | - Young Soon Yang
- Department of NeurologyNational Neuroscience InstituteSingaporeSingapore
| | - Dalla Yoo
- Department of NeurologyKyung Hee University HospitalSeoulSouth Korea
| | - Cheol‐Min Shin
- Division of Gastroenterology, Department of Internal MedicineSeoul National University Bundang HospitalSeongnamSouth Korea
| | - Hee Tae Kim
- Department of NeurologyHanyang University Medical CenterSeoulSouth Korea
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Jin M, Son M. DA-9701 (Motilitone): A Multi-Targeting Botanical Drug for the Treatment of Functional Dyspepsia. Int J Mol Sci 2018; 19:ijms19124035. [PMID: 30551633 PMCID: PMC6321359 DOI: 10.3390/ijms19124035] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 12/12/2022] Open
Abstract
Functional dyspepsia (FD) is the most common functional gastrointestinal disorder (FGID). FD is characterized by bothersome symptoms such as postprandial fullness, early satiety, and epigastric pain or burning sensations in the upper abdomen. The complexity and heterogeneity of FD pathophysiology, which involves multiple mechanisms, make both treatment and new drug development for FD difficult. Current medicines for FD targeting a single pathway have failed to show satisfactory efficacy and safety. On the other hand, multicomponent herbal medicines that act on multiple targets may be a promising alternative treatment for FD. DA-9701 (Motilitone), a botanical drug consisting of Corydalis Tuber and Pharbitidis Semen, has been prescribed for FD since it was launched in Korea in 2011. It has multiple mechanisms of action such as prokinetic effects, fundus relaxation, and visceral analgesia, which are mediated by dopamine D2 and several serotonin receptors involved in gastrointestinal (GI) functions. In clinical studies, DA-9701 has been found to be beneficial for improvement of FD symptoms and GI functions in FD patients, while showing better safety compared to that associated with conventional medicines. In this review, we provide updated information on the pharmacological effects, safety, and clinical results of DA-9701 for the treatment of FGIDs.
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Affiliation(s)
- Mirim Jin
- Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Korea.
- Department of Health Science and Technology, GAIHST, Gachon University, Incheon 21936, Korea.
| | - Miwon Son
- Research Center & Phytotherapeutics Group, Viromed, Co. Ltd., Seoul 08826, Korea.
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Kim SY, Woo HS, Kim KO, Choi SH, Kwon KA, Chung JW, Kim YJ, Kim JH, Kim SJ, Park DK. DA-9701 improves colonic transit time and symptoms in patients with functional constipation: A prospective study. J Gastroenterol Hepatol 2017; 32:1943-1948. [PMID: 28431454 DOI: 10.1111/jgh.13807] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 03/24/2017] [Accepted: 04/13/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM DA-9701, a newly developed prokinetic agent formulated with Pharbitis Semen and Corydalis Tuber, has been shown to effectively treat functional dyspepsia. Recently, it has also been suspected to improve gastrointestinal motor function. The aims of this study were to assess the effect of DA-9701 on colonic transit time (CTT) and symptoms of functional constipation. METHODS Thirty-three patients with functional constipation based on the Rome III criteria were prospectively enrolled. The patients received 30-mg DA-9701 three times a day for 24 days. CTT was estimated initially and at the end of treatment. Symptoms such as spontaneous bowel movements, straining, stool form, feeling of incomplete emptying and anorectal blockage, abdominal discomfort and pain, overall defecation satisfaction, and incidence of adverse events were also analyzed. RESULTS Twenty-seven patients completed the study. DA-9701 was associated with a significantly reduced CTT from 34.9 ± 17.6 to 23.7 ± 19.1 h (P = 0.001). Segmental CTT also significantly decreased after treatment (right CTT: from 16.8 [0.0-28.8] to 6.0 [0.0-25.2] hours, P < 0.001; rectosigmoid transit time: from 13.2 [0.0-38.4] to 6.0 [0.0-33.6] hours, P = 0.021). In addition, all constipation-related subjective symptoms, including spontaneous bowel movement frequency, significantly improved compared with those before treatment. Serious adverse events did not occur. CONCLUSIONS DA-9701 accelerates colonic transit and safely improves symptoms in patients with functional constipation. Therefore, we suggest that this novel agent could help to treat patients with this condition.
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Affiliation(s)
- Su Young Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Hyun Sun Woo
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Kyoung Oh Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Sung Han Choi
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Kwang An Kwon
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Jun-Won Chung
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Yoon Jae Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Jung Ho Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Su Ji Kim
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
| | - Dong Kyun Park
- Division of Gastroenterology, Department of Internal Medicine, Gachon University, Incheon, South Korea
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Jung HJ, Kang JH, Choi S, Son YK, Lee KR, Seong JK, Kim SY, Oh SH. Pharbitis Nil (PN) induces apoptosis and autophagy in lung cancer cells and autophagy inhibition enhances PN-induced apoptosis. JOURNAL OF ETHNOPHARMACOLOGY 2017; 208:253-263. [PMID: 28729229 DOI: 10.1016/j.jep.2017.07.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 07/10/2017] [Accepted: 07/15/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pharbitis Nil (PN) is used as a main component of the existing drug, DA-9701, which was developed to treat functional dyspepsia (FD) in Korea. PN extracts isolated from its seeds have been reported to have anticancer effects. AIM OF THE STUDY The purpose of this study was to investigate the underlying mechanism of the chemotherapeutic effects of PN in lung cancer cells. MATERIALS AND METHODS We performed MTT assays, colony formation assays, flow cytometry assays, Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence analysis, and cell counting assays to study the molecular mechanism of chemotherapeutic effects of PN in lung cancer cells. RESULTS Our results indicate that PN induced autophagy as well as apoptosis. PN inhibited cell proliferation and survival by inducing apoptosis in several lung cancer cell lines. PN-treated cells also exhibited induction of autophagy, as evidenced by increased protein expression levels and punctuate patterns of LC3 II. Moreover, activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which plays an important role in autophagy activation, was shown to be related with PN-induced autophagy. Interestingly, pharmacological blockade of autophagy activation with wortmannin and inhibition of ERK1/2 phosphorylation by U0126 markedly enhanced PN-induced apoptosis and reduced cell viability, suggesting that autophagy induced by PN may have a cytoprotective effect by suppressing apoptosis. PN- induced apoptosis was regulated by signal transducer and activator of transcription 3 (STAT3) deactivation. Moreover, decrease of STAT3 activation in PN-treated cells was associated with reduced survivin expression, further demonstrating that PN-induced apoptosis was regulated by STAT3 deactivation. CONCLUSION We believe that PN, which is already proven to treat human patients with FD, might be a potential anticancer drug for human lung cancer. In addition, our data suggest that the combination of PN treatment with an autophagy inhibitor or traditional anticancer agents may be an effective anticancer therapy.
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Affiliation(s)
- Hyun Jin Jung
- Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
| | - Ju-Hee Kang
- College of Pharmacy, Gachon University, 191, Hambangmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Seungho Choi
- College of Veterinary Medicine, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
| | - Youn Kyoung Son
- Biological and Genetic Resources Assessment Division, National Institute of Biological Resources, Incheon 22689, Republic of Korea
| | - Kang Ro Lee
- Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, Suwon 16419-16, Republic of Korea
| | - Je Kyung Seong
- Korea Mouse Phenotyping Center, College of Veterinary Medicine, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
| | - Sun Yeou Kim
- College of Pharmacy, Gachon University, 191, Hambangmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea
| | - Seung Hyun Oh
- College of Pharmacy, Gachon University, 191, Hambangmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea.
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Liu Q, Bi DY, Chen W, Wen WN, Chen W, Liu X, Chang XR, Zhang GS, Yuan ZY. Effect of Tongxie Yaofang on gastrointestinal motility, ultrastructure of interstitial cells of cajal and connexin 43 expression in rats with functional dyspepsia. Shijie Huaren Xiaohua Zazhi 2017; 25:974-982. [DOI: 10.11569/wcjd.v25.i11.974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of Tongxie Yaofang on gastrointestinal motility, the ultrastructure of interstitial cells of Cajal (ICC) and connexin 43 (Cx43) expression in functional dyspepsia (FD) rats.
METHODS FD was induced in rats by stimulating the rat tail using sponge forceps. FD rats were then treated with different doses of Tongxie Yaofang, with domperidone as a positive control. After treatment, rat appetite and weight were recorded. The rats were then sacrificed, and gastric emptying and intestinal transit were recorded. Transmission electron microscopy was used to observe the ultrastructure of ICC, and immunohistochemistry was used to detect the expression of Cx43 in gastrointestinal tissues of FD rats.
RESULTS After rats were stimulated using sponge forceps, they developed symptoms compatible with those of FD. The appetite and weight of FD rats were lower than those of normal controls, and the gastric emptying rate and intestinal transit rate were also significantly lower (p < 0.05 for both). After treatment with high-dose Tongxie Yaofang (3.412 g/kg) or domperidone, rat body weight, appetite, the gastric emptying rate and intestinal transit rate recovered to normal levels, although these were not fully achieved in rats treated with low- or medium dose Tongxie Yaofang (0.853 g/kg and 1.706 g/kg, respectively). Moreover, the altered ultrastructure of ICC and the decreased expression of Cx43 in the stomach and small intestine of FD rats were back to normal after treatment with high-dose Tongxie Yaofang (3.412 g/kg) or domperidone.
CONCLUSION Tongxie Yaofang (3.412 g/kg) has a positive effect on gastrointestinal motility in FD rats, and the underlying mechanism may be related to the modulation of ICC and Cx43 expression in gastrointestinal tissues.
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Lee SP, Lee OY, Lee KN, Lee HL, Choi HS, Yoon BC, Jun DW. Effect of DA-9701, a Novel Prokinetic Agent, on Post-operative Ileus in Rats. J Neurogastroenterol Motil 2017; 23:109-116. [PMID: 27832682 PMCID: PMC5216641 DOI: 10.5056/jnm16003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 05/23/2016] [Accepted: 10/11/2016] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Post-operative ileus (POI) is a common complication of abdominal surgery. DA-9701, an extract of Pharbitis Semen and Corydalis Tuber, is a new prokinetic agent that also alleviates visceral pain. The aim of this study was to investigate whether DA-9701 can ameliorate POI in rats. Methods A total of 32 rats were divided into 4 groups: no surgery/no medication (NSNM), no surgery/medication (NSM), surgery/no medication (SNM), and surgery/medication (SM). Gastrointestinal transit (GIT), which is assessed by migration of charcoal, and cumulative stool weight were measured at 24 hours after surgery. Results GIT was significantly more delayed in the SNM group than in the other groups (SNM vs NSNM, P < 0.001; SNM vs NSM, P < 0.001; SNM vs SM, P = 0.005). Cumulative stool weight in that group was also lower than in the no surgery groups (SNM vs NSNM, P = 0.007; SNM vs NSM, P = 0.033), and there was no significant difference between the SM group and the no surgery groups (SM vs NSM, P = 0.703; SM vs NSNM, P = 0.347). Conclusion DA-9701 can ameliorate POI by reducing delayed GIT and improving defecation in a rat model of POI.
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Affiliation(s)
- Sang Pyo Lee
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Kang Nyeong Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Hang Lak Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Ho Soon Choi
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Byung Chul Yoon
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
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Choi MG, Rhee PL, Park H, Lee OY, Lee KJ, Choi SC, Seol SY, Chun HJ, Rew JS, Lee DH, Song GA, Jung HY, Jeong HY, Sung IK, Lee JS, Lee ST, Kim SK, Shin YW. Randomized, Controlled, Multi-center Trial: Comparing the Safety and Efficacy of DA-9701 and Itopride Hydrochloride in Patients With Functional Dyspepsia. J Neurogastroenterol Motil 2015; 21:414-22. [PMID: 26130637 PMCID: PMC4496904 DOI: 10.5056/jnm14117] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 12/29/2014] [Accepted: 01/07/2015] [Indexed: 01/19/2023] Open
Abstract
Background/Aims Therapies of functional dyspepsia (FD) are limited. DA-9701 is a novel prokinetic agent formulated with Pharbitis semen and Corydalis Tuber. We aimed to assess the efficacy of DA-9701 compared with itopride in FD patients. Methods Patients with FD randomly received either itopride 50 mg or DA-9701 30 mg t.i.d after a 2-week baseline period. After 4 weeks of treatment, 2 primary efficacy endpoints were analyzed: the change from baseline in composite score of the 8 dyspeptic symptoms and the overall treatment effect. Impact on patients’ quality of life was assessed using the Nepean Dyspepsia Index (NDI) questionnaire. Results We randomly assigned 464 patients with 455 having outcome data. The difference of the composite score change of the 8 symptoms between the 2 groups was 0.62, indicating that DA-9701 was not inferior to itopride. The overall treatment effect response rate was not different between the groups. When responder was defined as ≥ 5 of the 7 Likert scale, responder rates were 37% of DA-9701 and 36% of itopride group. Patients receiving DA-9701 experienced similar mean percentage of days with adequate relief during the 4-week treatment period compared with those receiving itopride (56.8% vs 59.1%). Both drugs increased the NDI score of 5 domains without any difference in change of the NDI score between the groups. The safety profile of both drugs was comparable. Conclusions DA-9701 significantly improves symptoms in patients with FD. DA-9701 showed non-inferior efficacy to itopride with comparable safety.
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Affiliation(s)
- Myung-Gyu Choi
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | | | - Hyojin Park
- Yonsei University College of Medicine, Seoul, Korea
| | - Oh Young Lee
- Hanyang University College of Medicine, Seoul, Korea
| | - Kwang Jae Lee
- Ajou University School of Medicine, Suwon, Gyeonggi-do, Korea
| | - Suck Chei Choi
- Wonkwang University College of Medicine, Iksan, Jeollabuk-do, Korea
| | | | | | - Jong-Sun Rew
- Chonnam National University College of Medicine, Gwangju, Korea
| | - Dong Ho Lee
- Seoul National University College of Medicine, Seoul, Korea
| | - Geun Am Song
- Pusan National University College of Medicine, Busan, Korea
| | | | - Hyung Yong Jeong
- Chungnam National University College of Medicine, Daejeon, Korea
| | | | - Joon Seong Lee
- Soonchunhyang University College of Medicine, Seoul, Korea
| | - Soo Teik Lee
- Chonbuk National University College of Medicine, Jeonju, Jeollabuk-do, Korea
| | - Sung Kook Kim
- Kyungpook National University College of Medicine, Daegu, Korea
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11
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Ahn TS, Kim DG, Hong NR, Park HS, Kim H, Ha KT, Jeon JH, So I, Kim BJ. Effects of Schisandra chinensis extract on gastrointestinal motility in mice. JOURNAL OF ETHNOPHARMACOLOGY 2015; 169:163-169. [PMID: 25862968 DOI: 10.1016/j.jep.2015.03.071] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 03/02/2015] [Accepted: 03/13/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Schisandra chinensis (Turcz.) Baill. (SC) continues to be used as a traditional folk medicine in Asia, especially for the treatment of gastrointestinal (GI) disorders related to gastritis, diarrhea, enterocolitis and abnormal GI motility. AIM OF THE STUDY Because GI disorders, especially abnormal GI motility, are major lifelong problems, we investigated the effects of SC on the pacemaker activity of the interstitial cells of Cajal (ICCs) in murine small intestine and GI motility. MATERIALS AND METHODS Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials generated by cultured ICCs. In vivo effects of SC on GI motility were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal and GI motility dysfunction mice. RESULTS SC extracts depolarized the membrane potentials of ICCs in a dose dependent manner. Pretreatment with Ca(2+) free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in the endoplasmic reticulum) abolished the generation of pacemaker potentials by ICCs, and under these conditions, SC extract did not depolarize the membrane potentials of ICCs. In addition, membrane depolarizations were inhibited by intracellular GDPβS and by U-73122 (an active phospholipase C (PLC) inhibitor). In normal mice, ITRs were significantly increased by SC extract (0.1-1g/kg, intragastrically (i.g.)) in a dose dependent manner. Also, SC extract significantly recovered the GI motility dysfunctions in acetic acid (AA)-injected and streptozotocin (STZ)-induced diabetic mice, which are the GI motility animal models. MATERIALS AND METHODS SC extract modulates pacemaker potentials in ICCs in a dose dependent manner via external and internal Ca(2+) regulations, and via G protein and the PLC pathway. In addition, SC extract increased ITRs in normal and abnormal GI motility mice models. This study shows that SC extract offers a basis for the development of a prokinetic agent that prevents or alleviates GI motility dysfunctions.
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Affiliation(s)
- Tae Seok Ahn
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Dae Geon Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Noo Ri Hong
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Hyun Soo Park
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Hyungwoo Kim
- Division of Pharmacology, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Ki-Tae Ha
- Division of Applied Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
| | - Ju-Hong Jeon
- Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Insuk So
- Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea; Healthy Aging Korean Medical Research Center, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea.
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12
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Jung JW, Kwon YS, Jeong JS, Son M, Kang HE. Pharmacokinetics and Brain Distribution of Tetrahydropalmatine and Tetrahydroberberine after Oral Administration of DA-9701, a New Botanical Gastroprokinetic Agent, in Rats. Biol Pharm Bull 2015; 38:285-91. [DOI: 10.1248/bpb.b14-00678] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Ji Won Jung
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea
| | | | | | - Miwon Son
- Research Center, Dong-A Pharmaceutical Co
| | - Hee Eun Kang
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea
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Jung JW, Choi MR, Kwon YS, Jeong JS, Son M, Kang HE. Gender differences in corydaline pharmacokinetics in rats. Xenobiotica 2014; 45:456-63. [DOI: 10.3109/00498254.2014.988772] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Hwang MW, Lee JH, Kim BJ. Carthami Flos Depolarizes the Interstitial Cells of Cajal and Increases the Motility in Gastrointestinal Tract. INT J PHARMACOL 2014; 10:248-257. [DOI: 10.3923/ijp.2014.248.257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Kim ER, Min BH, Lee TH, Son M, Rhee PL. Effect of DA-9701 on colorectal distension-induced visceral hypersensitivity in a rat model. Gut Liver 2014; 8:388-93. [PMID: 25071903 PMCID: PMC4113047 DOI: 10.5009/gnl.2014.8.4.388] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 05/22/2013] [Accepted: 07/07/2013] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS DA-9701 is a newly developed drug made from the vegetal extracts of Pharbitidis semen and Co-rydalis tuber. The aim of this study was to evaluate the effect of DA-9701 on colorectal distension (CRD)-induced visceral hypersensitivity in a rat model. METHODS Male Sprague-Dawley rats were subjected to neonatal colon irritation (CI) using CRD at 1 week after birth (CI group). At 6 weeks after birth, CRD was applied to these rats with a pressure of 20 to 90 mm Hg, and changes in the mean arterial pressure (MAP) were measured at baseline (i.e., without any drug administration) and after the administration of different doses of DA-9701. RESULTS In the absence of DA-9701, the MAP changes after CRD were significantly higher in the CI group than in the control group at all applied pressures. In the control group, MAP changes after CRD were not significantly affected by the administration of DA-9701. In the CI group, however, the administration of DA-9701 resulted in a significant decrease in MAP changes after CRD. The administration of DA-9701 at a dose of 1.0 mg/kg produced a more significant decrease in MAP changes than the 0.3 mg/kg dose. CONCLUSIONS The administration of DA-9701 resulted in a significant increase in pain threshold in rats with CRD-induced visceral hypersensitivity.
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Affiliation(s)
- Eun Ran Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Ho Lee
- Dong-A ST, Co., Ltd., Research Center, Yongin, Korea
| | - Miwon Son
- Dong-A ST, Co., Ltd., Research Center, Yongin, Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Jung JW, Kim JM, Jeong JS, Son M, Lee HS, Lee MG, Kang HE. Pharmacokinetics of chlorogenic acid and corydaline in DA-9701, a new botanical gastroprokinetic agent, in rats. Xenobiotica 2014; 44:635-43. [PMID: 24417753 DOI: 10.3109/00498254.2013.874610] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
1.Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported. The aim of the present study is to evaluate the pharmacokinetic properties CA and CRD following intravenous and oral administration of pure CA (1-8 mg/kg) or CRD (1.1-4.5 mg/kg) and their equivalent dose of DA-9701 to rats. 2. Dose-proportional AUC and dose-independent clearance (10.3-12.1 ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478-0.899%). 3. CRD showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of CRD following 4.5 mg/kg oral CRD (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of CRD as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure CRD. The greater oral AUC of CRD for DA-9701 than for pure CRD could be due to decreased hepatic and/or GI first-pass extraction of CRD by other components in DA-9701.
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Affiliation(s)
- Ji Won Jung
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea , Bucheon , South Korea and
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Kim BJ. Shengmaisan regulates pacemaker potentials in interstitial cells of cajal in mice. J Pharmacopuncture 2013; 16:36-42. [PMID: 25780681 PMCID: PMC4331980 DOI: 10.3831/kpi.2013.16.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 11/03/2013] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES Shengmaisan (SMS) is a traditional Chinese medicine prescription widely used for the treatment of diverse organs in Korea. The interstitial cells of Cajal (ICCs) are pacemaker cells that play an important role in the generation of coordinated gastrointestinal (GI) motility. We have aimed to investigate the effects of SMS in the ICCs in the mouse small intestine. METHODS To dissociate the ICCs, we used enzymatic digestions from the small intestine in a mouse. After that, the ICCs were identified immunologically by using the anti-c-kit antibody. In the ICCs, the electrophysiological whole-cell patch-clamp configuration was used to record pacemaker potentials in the cultured ICCs. RESULTS The ICCs generated pacemaker potentials in the mouse small intestine. SMS produced membrane depolarization with concentration-dependent manners in the current clamp mode. Pretreatment with a Ca(2+) free solution and thapsigargin, a Ca(2+)-ATPase inhibitor in the endoplasmic reticulum, stopped the generation of the pacemaker potentials. In the case of Ca(2+)-free solutions, SMS induced membrane depolarizations. However, when thapsigargin in a bath solution was applied, the membrane depolarization was not produced by SMS. The membrane depolarizations produced by SMS were inhibited by U-73122, an active phospholipase C (PLC) inhibitors. Furthermore, chelerythrine and calphostin C, a protein kinase C (PKC) inhibitors had no effects on SMS-induced membrane depolarizations. CONCLUSIONS These results suggest that SMS might affect GI motility by modulating the pacemaker activity through an internal Ca(2+)- and PLC-dependent and PKC-independent pathway in the ICCs.
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Affiliation(s)
- Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Korea
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Kwon YS, Son M. DA-9701: A New Multi-Acting Drug for the Treatment of Functional Dyspepsia. Biomol Ther (Seoul) 2013; 21:181-9. [PMID: 24265862 PMCID: PMC3830115 DOI: 10.4062/biomolther.2012.096] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 03/12/2013] [Accepted: 03/14/2013] [Indexed: 12/17/2022] Open
Abstract
Motilitone® (DA-9701) is a new herbal drug that was launched for the treatment of functional dyspepsia in December 2011 in Korea. The heterogeneous symptom pattern and multiple causes of functional dyspepsia have resulted in multiple drug target strategies for its treatment. DA-9701, a compound consisting of a combination of Corydalis Tuber and Pharbitidis Semen, has being developed for treatment of functional dyspepsia. It has multiple mechanisms of action such as fundus relaxation, visceral analgesia, and prokinetic effects. Furthermore, it was found to significantly enhance meal-induced gastric accommodation and increase gastric compliance in dogs. DA-9701 also showed an analgesic effect in rats with colorectal distension induced visceral hypersensitivity and an antinociceptive effect in beagle dogs with gastric distension-induced nociception. The pharmacological effects of DA-9701 also include conventional effects, such as enhanced gastric emptying and gastrointestinal transit. The safety profi le of DA-9701 is also preferable to that of other treatments.
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Affiliation(s)
- Yong Sam Kwon
- Dong-A ST Research Institute, Yongin 446-905, Republic of Korea
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Lee SP, Lee KN, Lee OY, Lee HL, Jun DW, Yoon BC, Choi HS, Hwang SJ, Lee SE. Effects of DA-9701, a novel prokinetic agent, on phosphorylated extracellular signal-regulated kinase expression in the dorsal root ganglion and spinal cord induced by colorectal distension in rats. Gut Liver 2013; 8:140-7. [PMID: 24672654 PMCID: PMC3964263 DOI: 10.5009/gnl.2014.8.2.140] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2013] [Revised: 04/11/2013] [Accepted: 04/15/2013] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS DA-9701, a standardized extract of Pharbitis Semen and Corydalis Tuber, is a new prokinetic agent that exhibits an analgesic effect on the abdomen. We investigated whether DA-9701 affects visceral pain induced by colorectal distension (CRD) in rats. METHODS A total of 21 rats were divided into three groups: group A (no CRD+no drug), group B (CRD+no drug), and group C (CRD+DA-9701). Expression of pain-related factors, substance P (SP), c-fos, and phosphorylated extracellular signal-regulated kinase (p-ERK) in the dorsal root ganglion (DRG) and spinal cord was determined by immunohistochemical staining and Western blotting. RESULTS The proportions of neurons in the DRG and spinal cord expressing SP, c-fos, and p-ERK were higher in group B than in group A. In the group C, the proportion of neurons in the DRG and spinal cord expressing p-ERK was lower than that in group B. Western blot results for p-ERK in the spinal cord indicated a higher level of expression in group B than in group A and a lower level of expression in group C than in group B. CONCLUSIONS DA-9701 may decrease visceral pain via the downregulation of p-ERK in the DRG and spinal cord.
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Affiliation(s)
- Sang Pyo Lee
- Department of Internal Medicine, Digestive Disease Centre, Konkuk University School of Medicine, Seoul, Korea
| | - Kang Nyeong Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Hang Lak Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Byung Chul Yoon
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Ho Soon Choi
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Se Jin Hwang
- Department of Anatomy & Cell Biology, Hanyang University College of Medicine, Seoul, Korea
| | - Seo Eun Lee
- Department of Physiology, Hanyang University College of Medicine, Seoul, Korea
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Kim BJ, Kim HW, Lee GS, Choi S, Jun JY, So I, Kim SJ. Poncirus trifoliate fruit modulates pacemaker activity in interstitial cells of Cajal from the murine small intestine. JOURNAL OF ETHNOPHARMACOLOGY 2013; 149:668-675. [PMID: 23911946 DOI: 10.1016/j.jep.2013.07.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 07/02/2013] [Accepted: 07/11/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Poncirus fructus (PF) has been widely used as a traditional medicine in Eastern Asia, especially to ameliorate the symptoms of gastrointestinal (GI) disorders related to abnormal GI motility. AIM OF THE STUDY Poncirus fructus (PF), also known as Poncirus trifoliata (L.) Raf. (Rutaceae), is widely used as a traditional medicine in Eastern Asia mainly to ameliorate the symptoms of gastrointestinal (GI) disorders related to abnormal GI motility. In a previous study, a methanol extract of PF was found to have particularly potent gastroprokinetic effects. Interstitial cells of Cajal (ICCs) are pacemaker cells in the gastrointestinal tract, but the action mechanisms of PF extract in mouse small intestinal ICCs have not been investigated. Therefore, in the present study, we investigated the effects of a methanol extract of PF (MPF) in mouse small intestinal ICCs. In addition, we sought to identify the receptors involved. MATERIALS AND METHODS Enzymatic digestions were used to dissociate ICCs from small intestines. The whole-cell patch-clamp configuration was used to record potentials (current clamp) from cultured ICCs. In addition, we analyzed intracellular Ca(2+) concentrations ([Ca(2+)]i). RESULTS MPF decreased the amplitudes of pacemaker potentials in ICCs, and depolarized resting membrane potentials in a concentration dependent manner. Y25130 (a 5-HT3 receptor antagonist) and RS39604 (a 5-HT4 receptor antagonist) blocked MPF-induced membrane depolarizations, whereas SB269970 (a 5-HT7 receptor antagonist) did not. Pretreatment with Na(+) or Ca(2+)-free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in endoplasmic reticulum) abolished the generation of pacemaker potentials and suppressed MPF-induced activity. [Ca(2+)]i analysis showed that MPF increased [Ca(2+)]i. Furthermore, treatments with PD 98059, SB203580, or JNK II inhibitor blocked MPF-induced membrane depolarizations in ICCs. CONCLUSION These results suggest that MPF modulates pacemaker potentials through 5-HT3 and 5-HT4 receptor-mediated pathways via external Na(+) and Ca(2+) influx, and via Ca(2+) release from internal stores in a mitogen-activated protein kinase dependent manner. The study shows MPF is a good candidate for the development of a gastroprokinetic agent. In view of the effects of MPF on ICCs, further research is required, particularly to identify the active compound(s) involved and to determine their action mechanisms.
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Affiliation(s)
- Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea
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Kim JN, Song HJ, Lim B, Kwon YK, Kim BJ. Modulation of pacemaker potentials by pyungwi-san in interstitial cells of cajal from murine small intestine: pyungwi-san and interstitial cells of cajal. J Pharmacopuncture 2013; 16:43-49. [PMID: 25780661 PMCID: PMC4331954 DOI: 10.3831/kpi.2013.16.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 11/28/2012] [Indexed: 11/09/2022] Open
Abstract
OBJECTIVE Pyungwi-san (PWS) plays a role in a number of physiologic and pharmacologic functions in many organs. Interstitial cells of Cajal (ICCs) are pacemaker cells that generate slow waves in the gastrointestinal (GI) tract. We aimed to investigate the beneficial effects of PWS in mouse small-intestinal ICCs. METHODS Enzymatic digestion was used to dissociate ICCs from the small intestine of a mouse. The wholecell patch-clamp configuration was used to record membrane potentials from the cultured ICCs. RESULTS ICCs generated pacemaker potentials in the GI tract. PWS produced membrane depolarization in the current clamp mode. Pretreatment with a Ca(2+) -free solution and a thapsigargin, a Ca(2+) -ATPase, inhibitor in the endoplasmic reticulum, eliminated the generation of pacemaker potentials. However, only when the thapsigargin was applied in a bath solution, the membrane depolarization was not produced by PWS. Furthermore, the membrane depolarizations due to PWS were inhibited not by U-73122, an active phospholipase C inhibitor, but by chelerythrine and calphostin C, protein kinase C inhibitors. CONCLUSIONS These results suggest that PWS might affect GI motility by modulating the pacemaker activity in the ICCs.
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Affiliation(s)
- Jung Nam Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Korea
| | - Ho Jun Song
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Korea
| | - Bora Lim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Korea
| | - Young Kyu Kwon
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Korea
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Hwang MW, Kim JN, Song HJ, Lim B, Kwon YK, Kim BJ. Effects of Lizhong Tang on cultured mouse small intestine interstitial cells of Cajal. World J Gastroenterol 2013; 19:2249-2255. [PMID: 23599652 PMCID: PMC3627890 DOI: 10.3748/wjg.v19.i14.2249] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 02/06/2013] [Accepted: 02/08/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of Lizhong Tang, an herbal product used in traditional Chinese medicine, on mouse small intestine interstitial cells of Cajal (ICCs). METHODS Enzymatic digestions were used to dissociate ICCs from mouse small intestine tissues. The ICCs were morphologically distinct from other cell types in culture and were identified using phase contrast microscopy after verification with anti c-kit antibody. A whole-cell patch-clamp configuration was used to record potentials (current clamp) from cultured ICCs. All of the experiments were performed at 30-32 °C. RESULTS ICCs generated pacemaker potentials, and Lizhong Tang produced membrane depolarization in current-clamp mode. The application of flufenamic acid (a nonselective cation channel blocker) abolished the generation of pacemaker potentials by Lizhong Tang. Pretreatment with thapsigargin (a Ca²⁺-ATPase inhibitor in the endoplasmic reticulum) also abolished the generation of pacemaker potentials by Lizhong Tang. However, pacemaker potentials were completely abolished in the presence of an external Ca²⁺-free solution, and under this condition, Lizhong Tang induced membrane depolarizations. Furthermore, When GDP-β-S (1 mmol/L) was in the pipette solution, Lizhong Tang still induced membrane depolarizations. In addition, membrane depolarizations were not inhibited by chelerythrine or calphostin C, which are protein kinase C inhibitors, but were inhibited by U-73122, an active phospholipase C inhibitors. CONCLUSION These results suggest that Lizhong Tang might affect gastrointestinal motility by modulating pacemaker activity in interstitial cells of Cajal.
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Effect of a New Prokinetic Agent DA-9701 Formulated with Corydalis Tuber and Pharbitidis Semen on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:650718. [PMID: 22548118 PMCID: PMC3323859 DOI: 10.1155/2012/650718] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Accepted: 01/02/2012] [Indexed: 12/13/2022]
Abstract
DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC(50)) values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol 1'-hydroxylation with an inhibition constant (K(i)) value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol 1'-hydroxylation, with a K(i) value of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC(50) equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate the in vivo extent of the observed in vitro interactions.
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Lee TH, Son M, Kim SY. Effects of corydaline from Corydalis tuber on gastric motor function in an animal model. Biol Pharm Bull 2011; 33:958-62. [PMID: 20522959 DOI: 10.1248/bpb.33.958] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of this study was to evaluate the prokinetic and gastric-relaxing effects of the isoquinoline alkaloid corydaline, which was extracted from Corydalis tubers (CT). Corydaline is a marker compound used for quality control of DA-9701, a prokinetic agent formulated from extracts of Pharbitidis semen and Corydalis tuber that is currently in clinical trials in Korea for the treatment of functional dyspepsia (FD). DA-9701 was previously reported to be a potential therapeutic agent for the treatment of abnormalities in gastrointestinal motor function in FD patients; however, the therapeutic effects of corydaline on FD have yet to be demonstrated in an in vivo study. In the current study, oral administration of corydaline not only significantly accelerated gastric emptying in normal rats but also improved delayed gastric emptying to near normal levels. Furthermore, corydaline induced significant gastric relaxation, shifting the pressure-volume curve towards higher volumes compared to controls. These results suggest that corydaline promotes gastric emptying and small intestinal transit and facilitates gastric accommodation.
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Affiliation(s)
- Tae Ho Lee
- Research Center, Dong-A Pharm. Co., Ltd., Gyeonggi-do 446-905, Republic of Korea
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Wang ZY, Xu WX. Advances in research on pacemaking function of gastrointestinal smooth muscle cells. Shijie Huaren Xiaohua Zazhi 2010; 18:319-323. [DOI: 10.11569/wcjd.v18.i4.319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal smooth muscle has spontaneous contractile activity, which is very important to digestion and absorption function. However, the pacemaking mechanism in gastrointestinal smooth muscle is still not clear. In this article, we review the recent advances in research on the mechanisms underlying gastrointestinal pacemaker activity. We summarize the classification, function and pacemaking mechanisms of pacemaker cells, and the relationship between pacemaker cells and gastrointestinal motility dysfunction. As abnormal pacemaking activity is often associated with gastrointestinal motility dysfunction, it is of great clinical significance to clarify the pacemaking mechanisms in the gastrointestinal tract.
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