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Biomedicine & Pharmacotherapy =... Jun 2021Constipation, mainly characterized by the difficulty in defecation, is a clinical symptom caused by a variety of factors. It can be manifested as normal or slow colonic...
BACKGROUND
Constipation, mainly characterized by the difficulty in defecation, is a clinical symptom caused by a variety of factors. It can be manifested as normal or slow colonic transport abnormalities, which can occur alone or concurrently with defecation disorders. As there is not uniform definition and assessment standard, no clear plan could be used for the treatment of constipation. Although rhubarb, a traditional Chinese medicine, plays a therapeutic role in diseases involving constipation symptoms, the detailed mechanism of it in treating constipation remains unclear.
METHODS
A model of constipation-induced by diphenoxylate was prepared. Immunofluorescent staining was used to detect the expression of mucin 2 (MUC2), calnexin and chymase in colon. Western blotting was used to detect changes of tryptase and calnexin in the colon. And real-time polymerase chain reaction (PCR) was utilized to detect the changes of immunoglobulin-binding protein (Bip), X-box binding protein 1 (Xbp1) and C/EBP homologous protein (CHOP) of colonic goblet cells in mRNA levels. ELISA and biochemical kits were utilized to detect the changes of MUC2, Trefoil factor 3 (TFF3), acetylcholine, histamine and C-C motif chemokine ligand 5 (CCL5) in the colon. And the changes of colonic mucosa and intestinal flora of constipation model mice caused by rhubarb extract (RE) were analyzed to identify the mechanism of RE on the treatment of constipation.
RESULTS
RE promotes the secretion of colonic mucus by recruiting mast cells and enhancing the content of histamine and Ach in the mice colon. In the process, RE causes up-regulation of Bip and CHOP mRNA expression and down-regulation of Xbp1 and Xbp1s mRNA expression that induces ER stress of colonic epithelium associated with changes in the intestinal flora diversity and short-chain fatty acids content.
CONCLUSION
RE could relieve constipation by promoting the secretion of colonic mucus via mast cells activation and improving the intestinal microenvironment.
Topics: Animals; Colon; Constipation; Gastrointestinal Microbiome; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Mucus; Plant Extracts; Rheum
PubMed: 33774313
DOI: 10.1016/j.biopha.2021.111479 -
Journal of the American College of... Jun 2023Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide...
BACKGROUND
Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied.
OBJECTIVES
In this study, we sought to explore opioid-associated arrhythmia reporting in North America.
METHODS
The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory.
RESULTS
Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS.
CONCLUSIONS
The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.
Topics: Humans; Analgesics, Opioid; Diphenoxylate; Loperamide; Naltrexone; Arrhythmias, Cardiac; Buprenorphine; Methadone; Nonprescription Drugs
PubMed: 37286256
DOI: 10.1016/j.jacc.2023.04.009 -
Nutrients Aug 2023Slow transit constipation (STC) is a prevalent gastrointestinal condition with slow transit, and some probiotics can effectively relieve constipation, but the exact...
Slow transit constipation (STC) is a prevalent gastrointestinal condition with slow transit, and some probiotics can effectively relieve constipation, but the exact mechanisms have not been fully understood. In this study, we evaluate the impact of GUANKE (GUANKE) on diphenoxylate-induced slow transit constipation and speculate on the underlying mechanisms in a mouse model. Administration of GUANKE alleviated constipation indexes, including defecation time, fecal output and water content, and gastrointestinal transit ratio. In addition, GUANKE restored the protein expression of constipation-related intestinal factors (aquaporins (AQPs) and interstitial Cajal cells (ICCs)) in colon tissues measured using immunofluorescence staining; regulated the neurotransmitters and hormones, such as increased levels of 5-hydroxytryptamine, substance P, and motilin; and decreased levels of vasoactive intestinal peptide and nitric oxide in serum, as measured by an ELISA. 16S rRNA and correlation analysis of feces indicated that GUANKE administration effectively reduced constipation-induced enrichment and suggested a potential contribution of to diphenoxylate-induced STC in mice. GUANKE had no effect on short-chain fatty acids (SCFAs) in cecum content. This study revealed that GUANKE may alleviate constipation in mice through regulating intestinal neurotransmitter and hormone release and altering specific bacterial taxa, rather than by affecting SCFAs and the diversity of microbiota in the gut. Further research is needed to confirm if the findings observed in this study will be consistent in other animal studies or clinical trials.
Topics: Animals; Mice; Gastrointestinal Microbiome; Diphenoxylate; RNA, Ribosomal, 16S; Constipation
PubMed: 37686774
DOI: 10.3390/nu15173741 -
JCO Oncology Practice Feb 2022The financial toxicity of anticancer drugs is well-documented, but little is known about the costs of drugs used to manage cancer-associated symptoms. (Review)
Review
PURPOSE
The financial toxicity of anticancer drugs is well-documented, but little is known about the costs of drugs used to manage cancer-associated symptoms.
METHODS
We reviewed relevant guidelines and compiled drugs used to manage seven cancer-associated symptoms (anorexia and cachexia, chemotherapy-induced peripheral neuropathy, constipation, diarrhea, exocrine pancreatic insufficiency, cancer-associated fatigue, and chemotherapy-induced nausea and vomiting). Using GoodRx website, we identified the retail price (cash price at retail pharmacies) and lowest price (discounted, best-case scenario of out-of-pocket costs) for patients without insurance for each drug or formulation for a typical fill. We describe lowest prices here.
RESULTS
For anorexia and cachexia, costs ranged from $5 US dollars (USD; generic olanzapine or mirtazapine tablets) to $1,156 USD (brand-name dronabinol solution) and varied widely by formulation of the same drug or dosage: for olanzapine 5 mg, $5 USD (generic tablet) to $239 USD (brand-name orally disintegrating tablet). For chemotherapy-induced peripheral neuropathy, costs of duloxetine varied from $12 USD (generic) to $529 USD (brand-name). For constipation, the cost of sennosides or polyethylene glycol was <$15 USD, whereas newer agents such as methylnaltrexone were expensive ($1,001 USD). For diarrhea, the cost of generic loperamide or diphenoxylate-atropine tablets was <$15 USD. For exocrine pancreatic insufficiency, only brand-name formulations were available, range of cost, $1,072 USD-$1,514 USD. For cancer-associated fatigue, the cost of generic dexamethasone or dexmethylphenidate was <$15 USD, whereas brand-name modafinil was more costly ($1,284 USD). For a 4-drug nausea and vomiting prophylaxis regimen, costs ranged from $181 USD to $1,430 USD.
CONCLUSION
We highlight the high costs of many symptom control drugs and the wide variation in the costs of these drugs. These findings can guide patient-clinician discussions about cost-effectively managing symptoms, while promoting the use of less expensive formulations when possible.
Topics: Antineoplastic Agents; Drug Costs; Drugs, Generic; Financial Stress; Humans; Neoplasms; Pharmacies
PubMed: 34558297
DOI: 10.1200/OP.21.00466 -
Journal of Integrative Medicine Jul 2023Abnormalities in the gut microbiota and intestinal short-chain fatty acid (SCFA) levels are implicated in the pathogenesis of functional constipation (FC)....
OBJECTIVE
Abnormalities in the gut microbiota and intestinal short-chain fatty acid (SCFA) levels are implicated in the pathogenesis of functional constipation (FC). Electro-acupuncture (EA) has been shown to improve constipation-related symptoms and rebalance the gut microbiota. However, it is currently unknown whether the gut microbiota is a key mechanistic target for EA or how EA promotes gut motility by regulating the gut microbiota and SCFAs. Therefore, we assessed the effects of EA in FC mice and pseudo-germfree (PGF) mice to address these questions.
METHODS
Forty female Kunming mice were randomly separated into a normal control group (n = 8), an FC group (n = 8), an FC + EA group (n = 8), a PGF group (n = 8) and a PGF + EA group (n = 8). The FC group and FC + EA group were treated with diphenoxylate to establish the FC model; the PGF group and PGF + EA group were given an antibiotic cocktail to initiate the PGF model. After maintaining the model for 14 d, mice in the FC + EA and PGF + EA groups received EA stimulation at the ST25 and ST37 acupoints, once a day, 5 times per week, for 2 weeks. Fecal parameters and intestinal transit rate were calculated to assess the efficacy of EA on constipation and gastrointestinal motility. Colonic contents were used to quantify gut microbial diversity using 16S rRNA sequencing, and measure SCFA concentrations using gas chromatography-mass spectrometry.
RESULTS
EA significantly shortened the first black stool defecation time (P < 0.05) and increased the intestinal transit rate (P < 0.01), and fecal pellet number (P < 0.05), wet weight (P < 0.05) and water content (P < 0.01) over 8 h, compared with the FC group, showing that EA promoted gut motility and alleviated constipation. However, EA treatment did not reverse slow-transit colonic motility in PGF mice (P > 0.05), demonstrating that the gut microbiota may play a mechanistic role in the EA treatment of constipation. In addition, EA treatment restored the Firmicutes to Bacteroidetes ratio and significantly increased butyric acid generation in FC mice (P < 0.05), most likely due to the upregulation of Staphylococcaceae microorganisms (P < 0.01).
CONCLUSION
EA-mediated resolution of constipation occurs through rebalancing the gut microbiota and promoting butyric acid generation. Please cite this article as: Xu MM, Guo Y, Chen Y, Zhang W, Wang L, Li Y. Electro-acupuncture promotes gut motility and alleviates functional constipation by regulating gut microbiota and increasing butyric acid generation in mice. J Integr Med. 2023; Epub ahead of print.
Topics: Mice; Female; Animals; Gastrointestinal Microbiome; Butyric Acid; RNA, Ribosomal, 16S; Constipation; Acupuncture Therapy; Electroacupuncture
PubMed: 37331860
DOI: 10.1016/j.joim.2023.05.003 -
Food & Function Oct 2020The prebiotics inulin (INU) and isomalto-oligosaccharide (IMO) influence intestinal health and immunity, but their effects on constipation are not clearly established....
Effects of inulin and isomalto-oligosaccharide on diphenoxylate-induced constipation, gastrointestinal motility-related hormones, short-chain fatty acids, and the intestinal flora in rats.
The prebiotics inulin (INU) and isomalto-oligosaccharide (IMO) influence intestinal health and immunity, but their effects on constipation are not clearly established. We evaluated the effects of INU and IMO in a rat model of diphenoxylate-induced constipation. Twenty-four male rats were divided into four groups: basal diet (Con), 40 mg kg-1 diphenoxylate (PCon), 20 g kg-1 INU and treated with 40 mg kg-1 diphenoxylate, and 20 g kg-1 IMO and treated with 40 mg kg-1 diphenoxylate. INU and IMO increased the number, weight, and water content of fecal pellets, and decreased the time to the first black stool in rats with constipation. Serum levels of the gastrointestinal motility-related hormones adrenocorticotropic hormone (ACTH), motilin (MTL), and Substance P (SP) were higher and corticosterone (CORT), vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP) were lower in rats treated with prebiotics than in untreated rats. Colon tissue levels of MTL and SP were increased, and VIP and CGRP were decreased by prebiotics. Furthermore, in rats with constipation, INU and IMO increased the colonic contents of short-chain fatty acids. The relative abundance of Bacteroidetes was lower in the prebiotics groups than in the Con and PCon groups. Lactobacillus was more abundant in the INU and IMO groups than in PCon rats. Lactobacillus reuteri and Lactobacillus intestinalis were more abundant in the IMO group than in the PCon group (P < 0.01), and L. intestinalis was more abundant in the INU group than in the PCon group (P < 0.01). In summary, INU and IMO improved constipation and altered the intestinal microbiota in a rat model of constipation.
Topics: Animals; Bacteria; Constipation; Diphenoxylate; Fatty Acids, Volatile; Feces; Gastrointestinal Hormones; Gastrointestinal Microbiome; Gastrointestinal Motility; Humans; Intestines; Inulin; Male; Oligosaccharides; Prebiotics; Rats
PubMed: 33030479
DOI: 10.1039/d0fo00865f