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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 -
Luminescence : the Journal of... Jun 2024In this study, a chemiluminescence (CL) method was developed to determine diphenoxylate in tablets and human plasma. This is the first CL method proposed to determine...
In this study, a chemiluminescence (CL) method was developed to determine diphenoxylate in tablets and human plasma. This is the first CL method proposed to determine diphenoxylate. Creating three-dimensional data caused the parallel factor analysis algorithm (PARAFAC) to be used for the first time in CL methods. The method is based on the fact that diphenoxylate enhances the weak CL produced in the reaction of Ru(phen) and acidic Ce(IV), and the concentration of Ce(IV) solution has a different effect on the CL response of diphenoxylate and the blank plasma. The calibration curve was linear from 4.0 × 10 to 1.6 × 10 mol L (R = 0.9954), and the detection limit was 1.3 × 10 mol L (S/N = 3). The sampling rate was about 30 samples per hour, and the % RSD for 10 repeated measurements of 4 × 10 mol L diphenoxylate was 5.4%. The interference effects of some ions, amino acids, and common additives were also investigated. The CL method was successfully used to determine diphenoxylate in tablets, and the results were statistically confirmed by the reference method. The proposed CL method and the PARAFAC algorithm were successfully used to determine the concentration of diphenoxylate in human blood plasma samples.
Topics: Humans; Tablets; Luminescent Measurements; Luminescence; Limit of Detection; Algorithms; Oxalates; Factor Analysis, Statistical
PubMed: 38859619
DOI: 10.1002/bio.4805 -
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 -
Digestive Diseases and Sciences Dec 2019
Review
Topics: Antidiarrheals; Autonomic Nervous System Diseases; Blind Loop Syndrome; Celiac Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Diagnosis, Differential; Diarrhea; Diphenoxylate; Enteric Nervous System; Exocrine Pancreatic Insufficiency; Gastrointestinal Agents; Gastrointestinal Motility; Hypoglycemic Agents; Imidazoles; Inflammation; Inflammatory Bowel Diseases; Interstitial Cells of Cajal; Intestinal Absorption; Intestinal Mucosa; Irritable Bowel Syndrome; Loperamide; Neuroglia; Non-Nutritive Sweeteners; Oxidative Stress; Phenylalanine; Serotonin 5-HT3 Receptor Antagonists
PubMed: 31541370
DOI: 10.1007/s10620-019-05846-6 -
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 -
International Journal of Biological... Feb 2024Chronic constipation has been associated with depression-like behavior. Previous study identified the crucial role of gut microbiota in the development of constipation...
Chronic constipation has been associated with depression-like behavior. Previous study identified the crucial role of gut microbiota in the development of constipation and depression. Dietary inulin (INU) could regulate gut microbiota. Whether INU treatment could ameliorate constipation induced depression was not clear. For this purpose, male CD-1 mice were administered diphenoxylate (20 mg/kg body weight/day) to induce constipation. We found that INU (10 % in standard diet) alleviated the diphenoxylate-induced constipation, manifested as the increase weight and moisture content of feces. Furthermore, the associated depression and anxiety-like behavior disorders were improved by inhibiting neuro-inflammation and preventing synaptic ultrastructure damage under INU treatment. Moreover, INU pretreatment improved the diphenoxylate-induced gut barrier damage by upregulating tight junction protein expression. INU also reshaped gut microbiota in constipation mice by increasing the relative abundance of Bacteroides and Proteobacteria and downregulating the abundance of Muribacalum and Melaminabacteria. The effects of INU on diphenoxylate-induced depression were abolished by gut microbiota depletion via antibiotic treatment. In addition, INU increased the concentration of short chain fatty acids (SCFAs) in feces contents. Meanwhile, supplementation of SCFAs could also partly improve diphenoxylate-induced depression. In conclusion, INU intake was a potential nutritional intervention strategy to prevent constipation induced depression via microbiota-gut-SCFAs axis.
Topics: Male; Mice; Animals; Inulin; Gastrointestinal Microbiome; Depression; Diphenoxylate; Fatty Acids, Volatile; Constipation; Diet; Anxiety
PubMed: 38219945
DOI: 10.1016/j.ijbiomac.2024.129420 -
Current Opinion in Gastroenterology May 2024Chronic diarrhea is a common disorder that interferes with normal daily activities and results in poor quality of life. Fecal urgency and incontinence often necessitate... (Review)
Review
PURPOSE OF REVIEW
Chronic diarrhea is a common disorder that interferes with normal daily activities and results in poor quality of life. Fecal urgency and incontinence often necessitate clinical consultation, but the pathophysiological mechanisms are difficult to differentiate in a clinical setting. Therefore, drugs targeting the opioid receptors, such as diphenoxylate and loperamide, are typically used, as they reduce both gut motility and secretion.
RECENT FINDINGS
For severe diarrhea, morphine-containing extemporaneous opium tincture drops have recently been reprofiled to a pharmaceutical. The drug is indicated for severe diarrhea in adults when other antidiarrheals do not give sufficient fecal emptying control. The pronounced effect is due to the liquid formulation with rapid onset as a drug dissolution step is avoided. A recent prospective, noninterventional study (CLARIFY) of patients treated with opioid drops demonstrates a rapid and sustained therapeutic effect. Tolerance does not develop for the antidiarrheal effect and no dependence was observed after discontinuation.
SUMMARY
This mini-review discusses the use of opium derivates for treatment of diarrhea, with an emphasis on opium drops as a new medicinal grade opium for the use as additional treatment of severe diarrhea, emphasizing its mechanism of action and evaluation of the risk-benefit ratio in the clinical setting.
Topics: Adult; Humans; Opium; Quality of Life; Diarrhea; Antidiarrheals; Loperamide; Observational Studies as Topic
PubMed: 37903075
DOI: 10.1097/MOG.0000000000000985 -
Journal of Ethnopharmacology Feb 2024Functional constipation (FC), characterized by chronic constipation, significantly impacts physiological function and induces psychological stress in patients. However,...
HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE
Functional constipation (FC), characterized by chronic constipation, significantly impacts physiological function and induces psychological stress in patients. However, current clinical treatment options for FC are currently limited. Cistanche deserticola, a traditional Chinese medicine that promotes intestinal moisture and bowel relaxation, contains cistanche total alditol extract (CTAE) as its primary active extract. However, the production of CTAE, its overall efficacy, and potential mechanisms for treating FC have yet to been investigated.
AIM OF THE STUDY
This study aimed to reveal the overall efficacy and potential mechanism of action of CTAE in rats with FC using a combination of stable preparation, pharmacodynamics, non-targeted metabolomics, bile acid metabolomics, and western blotting.
MATERIALS AND METHODS
Fourteen batches of CTAE underwent quality testing. A rat model of FC was developed using diphenoxylate tablets. The comprehensive pharmacodynamic effects of CTAE on FC were evaluated using fecal characteristics (wet weight, dry weight, and water content), intestinal transmission (colonic EMG amplitude, colonic EMG frequency, propulsion length, and propulsion rate), serum and colon biochemical indicators, distribution of interstitial cells of Cajal (ICC), and pathological examination. Non-targeted metabolomics was performed to assess the changes in endogenous metabolite profiles induced by CTAE. Bile acid metabolomics and western blotting analyses were employed to validate the potential mechanisms of action of CTAE.
RESULTS
CTAE, with a total content of betaine, mannitol, D-fructose, glucose, and sucrose of (75.67 ± 3.73) %, significantly enhanced intestinal transit, regulated neurotransmitters, increased the expression of c-kit in ICC, and alleviated intestinal inflammation in rats with FC. Non-targeted metabolomics revealed that CTAE significantly alleviated FC-induced metabolic disorders, mainly the biosynthesis of primary bile acids. Targeted metabolomic analysis confirmed that CTAE regulated FC-induced bile acid disorders. Western-blotting results confirmed that CTAE increased the expression of CYP8B1, FGF15, TGR5, and FXR, thereby modulating bile acid synthesis and enterohepatic circulation.
CONCLUSION
CTAE demonstrates significant therapeutic effects on FC, primarily through the regulation of bile acid synthesis and enterohepatic circulation. These findings provide a promising foundation for the development and clinical application of novel CATE-based drugs.
Topics: Humans; Rats; Animals; Cistanche; Sugar Alcohols; Constipation; Intestines; Bile Acids and Salts
PubMed: 37967778
DOI: 10.1016/j.jep.2023.117420 -
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 -
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