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Pharmaceutical Biology Dec 2021Wei Chang An (WCA) is a commercial prescription developed for the coordination of gastrointestinal movement.
CONTEXT
Wei Chang An (WCA) is a commercial prescription developed for the coordination of gastrointestinal movement.
OBJECTIVE
To investigate the role of WCA in the regulation of diarrhoea and constipation in rats.
MATERIAL AND METHODS
The diarrhoea and constipation models were prepared by gavage of and diphenoxylate hydrochloride. Rats were randomized equally ( = 6) into the normal group given saline daily, the positive group given Pinaverium Bromide (13.5 mg/kg) or Sennoside A (0.1 mg/kg) and three WCA-treated groups (22, 44, and 88 mg/kg) by gavage daily for 7 consecutive days. The effects of WCA were assessed by a series of faecal symptoms and histopathology. Gastrointestinal parameters were determined by ELISA. The effect of WCA on gastrointestinal tissues was evaluated by strip assay. Expression of ROCK-1 and MLCK was measured by RT-PCR and Western blotting.
RESULTS
Data from Bristol stool form scale, diarrhoea index, visceral sensitivity, defaecation time, and intestinal propulsive rate showed that WCA protected rats against diarrhoea and constipation ( < 0.01). The up-regulation of Substance P and 5-hydroxytryptamine in diarrhoea rats and down-regulation of Substance P and vasoactive intestinal polypeptide in constipation rats were inhibited by WCA ( < 0.05). WCA stimulated the gastrointestinal strip contractions but inhibited ACh-induced contractions ( < 0.01). The decreased ROCK-1 and MLCK expression in diarrhoea rats and increased in constipation rats were suppressed by WCA ( < 0.01).
CONCLUSIONS
WCA has both antidiarrhea and anti-constipation effects, suggesting its bidirectional role in gastrointestinal modulation, and providing evidence of WCA for irritable bowel syndrome treatment.
Topics: Animals; Constipation; Diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Gastrointestinal Motility; Irritable Bowel Syndrome; Male; Myosin-Light-Chain Kinase; Rats; Rats, Wistar; rho-Associated Kinases
PubMed: 34711130
DOI: 10.1080/13880209.2021.1991383 -
Evidence-based Complementary and... 2022Miller (Aloe) known as a common succulent perennial herb had been traditionally used in constipation for more than 1,000 years. Aloe contained anthraquinones and other...
Miller (Aloe) known as a common succulent perennial herb had been traditionally used in constipation for more than 1,000 years. Aloe contained anthraquinones and other active compounds which had laxative effect and could modulate constipation. However, the therapeutic effects and mechanisms of aloe in constipation were still unclear. To explore the therapeutic effects and mechanisms of aloe in treating constipation, we employed network pharmacology, molecular docking, and mice experiments in this study. Our network pharmacology indicated that beta-carotene, sitosterol, campest-5-en-3beta-ol, CLR, arachidonic acid, aloe-emodin, quercetin, and barbaloin were the main active ingredients of aloe in treating constipation. Besides, the MAPK signaling pathway was the principal pathway utilized by aloe in treating constipation. Molecular docking results revealed that beta-carotene and sitosterol were acting as interference factors in attenuating inflammation by binding to an accessory protein of ERK, JNK, AKT, and NF-B p65. Otherwise, in vivo experiments, we used diphenoxylate-induced constipation mice model to explore the therapeutic effects and mechanisms of aloe. Results showed that aloe modulated the constipation mice by reducing the discharge time of first melena, improving the fecal conditions, increasing the gastric intestinal charcoal transit ratio, and improving the intestinal secretion in small intestine. Besides, aloe played an important regulation in promoting intestinal motility sufficiency and the levels of neurotransmitters balance with 5-HT, SP, and VIP on constipation mice. Moreover, aloe significantly inhibited the mRNA and proteins expressions of ERK, JNK, AKT and NF-B p65 in colon. Our study proved that aloe could reverse diphenoxylate-induced changes relating to the intestinal motility, intestinal moisture, and inhibition of the MAPK (ERK, JNK)/AKT/NF-B p65 inflammatory pathway. Our study provided experimental evidences of the laxative effect of aloe, which was beneficial to the further research and development of aloe.
PubMed: 35571728
DOI: 10.1155/2022/6225758 -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... Nov 2022To investigate the effects of Mijian Daotong Bowel Suppository (MJDs) on the compound diphenoxylate induced constipation model of male rats and its mechanisms. Sixty...
To investigate the effects of Mijian Daotong Bowel Suppository (MJDs) on the compound diphenoxylate induced constipation model of male rats and its mechanisms. Sixty SD male rats were randomly divided into blank group, model group, positive group and MJDs group. The constipation model was established by using compound diphenoxylate gavage. The rats in blank group and model group were treated with saline by enema, the rats in positive group and MJDs group were given Kaisailu and honey decoction laxative suppository by enema, respectively, once a day for 10 days. The body weight, fecal water content, gastric emptying rate (GER) and carbon ink propulsion rate (CIPR) of rats were observed during modeling and administration. The effects of MJDs on the pathological changes of colon tissue in constipation rats were investigated by hematoxylin-eosin (HE) staining. The effect of MJDs on 5-hydroxytryptamine (5-HT) in the colon of constipation rats was investigated by ELISA kit. The effects of MJDs on the expressions of aquaporins 3 (AQP3) and aquaporins 4 (AQP4) in the colon of constipation rats were detected by immunohistochemistry. After 10 days of administration, compared with the blank group, the body weight, fecal water content, carbon ink propulsion rate and colon 5-HT content in the model group were decreased significantly, while the expression levels of AQP3 and AQP4 in the colon were increased significantly (<0.05, <0.01). Compared with the model group, the fecal water content and colon 5-HT content in the positive group were increased significantly, and the expressions of AQP3 and AQP4 in the colon were decreased significantly. The body weight, fecal water content and colon 5-HT content in the MJDs group were increased significantly, and the expressions of AQP3 and AQP4 was decreased significantly (<0.05, <0.01). Compared with the positive group, the fecal water content of the MJDs group was decreased significantly, and the expressions of AQP3 and AQP4 in the colon of the MJDs group was decreased significantly (<0.05, <0.01). Gastric emptying rate was not statistically significant difference between the groups. MJDs has good therapeutic effects on constipation, and its mechanisms may be related to up-regulating the content of 5-HT in the colon and down-regulating the expressions of AQP3 and AQP4 in the colon.
Topics: Male; Animals; Rats; Laxatives; Diphenoxylate; Serotonin; Constipation; Body Weight; Carbon; Aquaporins
PubMed: 37308434
DOI: 10.12047/j.cjap.6337.2022.141 -
Medeniyet Medical Journal Dec 2023Potentially inappropriate medications (PIM) is a crucial problem in the geriatric population. The amount of prescription and unadherence increase because of the...
OBJECTIVE
Potentially inappropriate medications (PIM) is a crucial problem in the geriatric population. The amount of prescription and unadherence increase because of the different problems encountered in cancer patients. Our aim was to evaluate the effects of PIM in patients with gastrointestinal system cancer and to investigate its relationship with chemotherapy side effects, mortality, and progression.
METHODS
This retrospective cohort study assessed 154 patients with gastrointestinal system cancer. Demographics and disease features, the presence of PIM according to the "TIME-to-STOP" criteria and baseline laboratory parameters were recorded. The effects of PIM on survival and adverse treatment events were evaluated.
RESULTS
66.9% of the cases were male and 33.1% were female. The mean age was 71.9±6.4 years. The most common side effects of chemotherapy are nausea, vomiting, kidney injury, and pain. The most frequently used prescriptions among the 98 PIMs were gliclazide, hyoscine N-butylbromide, simethicone, diphenoxylate atropine, and thiocolchicoside. PIM was detected in 68.1% of the participants. Chemotherapy side effects were more common in PIM group (p<0.001, odds ratio =5.6). PIM had no effect on mortality. Factors associated with mortality were age, stage, albumin, creatinine, operation history, and progression. A significant relationship was found between age, cancer stage, albumin, creatinine, operation history, and PIM in the regression model. There was no relationship between PIM and progression-free survival.
CONCLUSION
Chemotherapy toxicity may increase with PIM detected on diagnosis. We suggest that PIM is an important factor in predicting the side effects of chemotherapy and minimizing the adverse effects.
PubMed: 38148726
DOI: 10.4274/MMJ.galenos.2023.03063 -
Animal Models and Experimental Medicine Apr 2022We aimed to reveal the mechanism of functional constipation in the treatment of Atractylodes macrocephala Koidz. (AMK) and Paeonia lactiflora Pall. (PLP).
Network pharmacological prediction and molecular docking analysis of the combination of Atractylodes macrocephala Koidz. and Paeonia lactiflora Pall. in the treatment of functional constipation and its verification.
BACKGROUND
We aimed to reveal the mechanism of functional constipation in the treatment of Atractylodes macrocephala Koidz. (AMK) and Paeonia lactiflora Pall. (PLP).
METHODS
The main active ingredients of AMK and PLP were screened by the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform. A database of functional constipation targets was established by GeneCard and OMIM. An "ingredient-target" network map was constructed with Cytoscape software (version 3.7.1), and molecular docking analysis was performed on the components and genes with the highest scores. The rats in the normal group were given saline, and those in the other groups were given 10 mg/kg diphenoxylate once a day for 14 days. The serum and intestinal tissue levels of adenosine monophosphate (cAMP), protein kinase A (PKA), and adenylyl cyclase (AC) of the rats and aquaporin (AQP)1, AQP3, and AQP8 were measured.
RESULTS
AMK and PLP had a significant role in the regulation of targets in the treatment of functional constipation. After treatment with AMK, PLP, or mosapride, the serum and intestinal tissue levels of AC, cAMP, and PKA were significantly downregulated. Groups receiving AMK and PLP or mosapride exhibited a reduction in the level of AQP1, AQP3, and AQP8 to varying degrees.
CONCLUSION
Molecular docking analysis revealed that AMK and PLP had a significant role in the regulation of targets in the treatment of functional constipation. Studies have confirmed that AMK and PLP can also affect AC, cAMP, and PKA. AC, cAMP, and PKA in model rats were significantly downregulated. AQP expression is closely related to AC, cAMP, and PKA. AMK and PLP can reduce the expression of AQP1, AQP3, and AQP9 in the colon of constipated rats.
Topics: Animals; Aquaporins; Atractylodes; Constipation; Cyclic AMP-Dependent Protein Kinases; Medicine, Chinese Traditional; Molecular Docking Simulation; Paeonia; Rats
PubMed: 35451570
DOI: 10.1002/ame2.12226 -
Frontiers in Nutrition 2022Slow transit constipation (STC) is a common disorder in the digestive system. This study aimed to evaluate the effects of stachyose (ST) and Furu 2019 () alone or...
INTRODUCTION
Slow transit constipation (STC) is a common disorder in the digestive system. This study aimed to evaluate the effects of stachyose (ST) and Furu 2019 () alone or combined on diphenoxylate-induced constipation and explore the underlying mechanisms using a mouse model.
METHODS
ICR mice were randomly divided into five groups. The normal and constipation model groups were intragastrically administrated with PBS. The ST, , and synbiotic groups were intragastrically administrated with ST (1.5 g/kg body weight), alive (3 × 10 CFU/mouse), or ST + (1.5 g/kg plus 3 × 10 CFU/mouse), respectively. After 21 days of intervention, all mice except the normal mice were intragastrically administrated with diphenoxylate (10 mg/kg body weight). Defecation indexes, constipation-related intestinal factors, serum neurotransmitters, hormone levels, short-chain fatty acids (SCFAs), and intestinal microbiota were measured.
RESULTS
Our results showed that three interventions with ST, , and synbiotic combination (ST + . sakei) all alleviated constipation, and synbiotic intervention was superior to ST or alone in some defecation indicators. The RT-PCR and immunohistochemical experiment showed that all three interventions relieved constipation by affecting aquaporins (AQP4 and AQP8), interstitial cells of Cajal (SCF and c-Kit), glial cell-derived neurotrophic factor (GDNF), and Nitric Oxide Synthase (NOS). The three interventions exhibited a different ability to increase the serum excitatory neurotransmitters and hormones (5-hydroxytryptamine, substance P, motilin), and reduce the serum inhibitory neurotransmitters (vasoactive intestinal peptide, endothelin). The result of 16S rDNA sequencing of feces showed that synbiotic intervention significantly increased the relative abundance of beneficial bacteria such as , and regulated the gut microbes of STC mice. In conclusion, oral administration of ST or alone or combined are all effective to relieve constipation and the symbiotic use may have a promising preventive effect on STC.
PubMed: 36687730
DOI: 10.3389/fnut.2022.1039403 -
International Journal of Clinical and... 2015In order to investigate the effects of diphenoxylate on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the...
In order to investigate the effects of diphenoxylate on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of CYP2B6, CYP2D6, CYP2C19, CYP1A2, CYP3A4, CYP2C9. The rats were randomly divided into diphenoxylate group (Low, Medium, High) and control group. The diphenoxylate group rats were given 12, 24, 48 mg/kg (Low, Medium, High) diphenoxylate by continuous intragastric administration for 7 days. Six probe drugs bupropion, metroprolol omeprazole, phenacetin, testosterone and tolbutamide were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. Statistical pharmacokinetics difference for omeprazole, phenacetin and tolbutamide in rats were observed by comparing diphenoxylate group with control group. Continuous 7 days-intragastric administration of diphenoxylate induces the activities of CYP2C19, CYP1A2 and CYP2C9 of rats. Induction of drug metabolizing enzyme by diphenoxylate would reduce the efficacy of other drug. Additionally, high dosage diphenoxylate may cause hepatotoxicity.
PubMed: 26770498
DOI: No ID Found -
American Journal of Translational... 2022Constipation is a common gastrointestinal problem worldwide. Its impact on health can range from an unpleasant problem to being seriously troublesome. When lifestyle... (Review)
Review
Constipation is a common gastrointestinal problem worldwide. Its impact on health can range from an unpleasant problem to being seriously troublesome. When lifestyle modification fails to deal with constipation, laxatives are the mainstay of therapy. There are several types of laxatives currently available; however, there still remains a need for better laxatives because certain currently available laxatives are not appropriate for or accessible to some patients. Preclinical experiments to study the laxative potential of substances/products of interest are vital to improving that situation. The selection of appropriate experimental models for assessing the laxative activities of substances/products under investigation is crucial to achieving valid and meaningful results. This article provides a scoping review of the literature, outlining, and summarizing models currently being used in preclinical experiments assessing the laxative activities of substances/products under investigation. The review includes both screening models, e.g., the isolated organ bath system, fecal assessment and intestinal transit assay, and confirmation models, e.g., constipation models. Chemical substances/drugs used to induce constipation in constipation models, e.g., loperamide, diphenoxylate, montmorillonite, and clonidine, as well as standard laxative agents used as a positive control in experimental models, e.g., bisacodyl, carbachol, lactulose, sodium picosulfate, castor oil, phenolphthalein, and yohimbine, are described in detail. The purpose of this article is to assist researchers in the design and implementation of preclinical experimental models for assessing laxative activities of substances/products under investigation to achieve valid and meaningful preclinical results prior to experimentation in humans.
PubMed: 35273679
DOI: No ID Found -
British Journal of Pharmacology Feb 2017
Topics: Amides; Angiotensin-Converting Enzyme Inhibitors; Atropine; Central Nervous System; Diphenoxylate; Drug Combinations; History, 20th Century; History, 21st Century; Humans; Peptides; Peptidyl-Dipeptidase A
PubMed: 28116748
DOI: 10.1111/bph.13683 -
Frontiers in Nutrition 2022Foxtail millet () has a long history of treating gastrointestinal ailments in China; however, little is known about the functional mechanism driving its therapeutic...
Foxtail millet () has a long history of treating gastrointestinal ailments in China; however, little is known about the functional mechanism driving its therapeutic effects. The primary edible form of millet is porridge. This study investigates the effects of millet porridge on diphenoxylate-induced constipation and intestinal microflora in mice. Fifty mice were randomly divided into five groups: normal control group, constipation model group, and low-dose, medium-dose, and high-dose millet porridge groups. After 14 days of millet porridge gavage, constipation was induced and measured. The results showed that millet porridge prevented constipation by increasing the water content of feces, shortened the time of the first melena defecation, promoted gastric emptying, and improved the rate of gastrointestinal propulsion. Millet porridge also dose-dependently increased levels of and and decreased levels of , , and in the intestine. These results show that millet porridge could accelerate intestinal motility and change the proportions of intestinal flora and that it has a potent prebiotic effect.
PubMed: 36071942
DOI: 10.3389/fnut.2022.965687