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Laxative Effects of Yangyin Tongmi Capsule on a Model of Diphenoxylate-Induced Constipation in Mice.Evidence-based Complementary and... 2020Constipation is characterized by reduced number of bowel movements, dry stools, and difficult defecation. Yangyin Tongmi capsule (YTC), a traditional Chinese formula, is...
Constipation is characterized by reduced number of bowel movements, dry stools, and difficult defecation. Yangyin Tongmi capsule (YTC), a traditional Chinese formula, is used in the treatment of constipation, while the underlying mechanisms remain unknown. Herein, this work attempted to prove the effects of YTC on constipation treatment and its possible mechanisms. KM mice were randomly divided into four groups ( = 10/group) and treated with double distilled water (Control), diphenoxylate (Model: 10 mg/kg), or diphenoxylate plus low-dose YTC (L-YTC: 0.6 g/kg) or high-dose YTC (H-YTC: 1.2 g/kg). The data indicated that YTC can significantly shorten the discharge time of the first black stool, improve intestinal propulsion rate, and increase the water content and quantity of feces in mice. ELISA suggested that YTC regulate the content of intestinal hormones and neurotransmitters, such as motilin (MTL), gastrin (GT), somatostatin (SST), substance P (SP), acetylcholine (Ach), and nitric oxide (NO). The expression levels of aquaporin 3 (AQP3) and aquaporin 8 (AQP8) in the colon were examined by immunohistochemistry. In the meantime, the expression levels of P2X2, C-kit, and stem cell factor (SCF) in the colon were examined by western blot analysis. The results of this study suggest that YTC has mitigative effects on diphenoxylate-induced constipation by regulating the content of intestinal hormones and neurotransmitters and regulating the expression of related proteins in the colon.
PubMed: 32148532
DOI: 10.1155/2020/1471824 -
The Oncologist Aug 2019Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter...
BACKGROUND
Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome.
SUBJECTS, MATERIALS, AND METHODS
Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated.
RESULTS
Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4.
CONCLUSION
Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome.
IMPLICATIONS FOR PRACTICE
Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diarrhea; Female; Humans; Male; Malignant Carcinoid Syndrome; Middle Aged; Patient Safety; Phenylalanine; Pyrimidines; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome
PubMed: 30651397
DOI: 10.1634/theoncologist.2018-0236 -
Frontiers in Pharmacology 2021Poisoning is a type of accidental injury and it is considered a major public health problem worldwide. Oral drug poisoning in children is an important cause of...
Poisoning is a type of accidental injury and it is considered a major public health problem worldwide. Oral drug poisoning in children is an important cause of accidental injury and even death. It is a common critical emergency in the field of pediatrics. Once a child unintentionally takes an overdose, regardless of whether it caused poisoning or not, they should be admitted to the hospital for emergency treatment. Acute poisoning in children most frequently occurs through the digestive tract. Drug poisoning can happen in children of all ages. In children younger than 1 year, drug poisoning is mostly caused by the parents during feeding, while in children aged 1-3 years, it predominantly occurs as a result of an accident. A case of diagnosis and treatment of a child with diphenoxylate-atropine poisoning is reported herein. The early manifestation of this child was acute toxic encephalopathy with clinical manifestations of a coma, convulsions, and respiratory depression. A brain MRI showed extensive damage to the bilateral caudate nucleus, lenticular nucleus, parietal lobe, precuneus lobe, and occipital lobe. Accidental administration of a large dose of diphenoxylate results in severe clinical symptoms and can cause obvious diffuse brain damage.
PubMed: 33912057
DOI: 10.3389/fphar.2021.646530 -
Frontiers in Pharmacology 2022Constipation is a common syndrome and a worldwide healthy problem. Constipation patients are becoming younger, with a 29.6% overall prevalence in children, which has...
Constipation is a common syndrome and a worldwide healthy problem. Constipation patients are becoming younger, with a 29.6% overall prevalence in children, which has captured significant attention because of its epigenetic rejuvenation and recurrent episodes. Despite the usage of rhubarb extract to relieve constipation, novel targets and genes implicated in target-relevant pathways with remarkable functionalities should still be sought for. We established a reliable constipation model in C57B/6N male mice using intragastric administration diphenoxylate, and the eligible subjects received 600 mg/25 g rhubarb extract to alleviate constipation. Resultant constipation was morphological and genetically compared with the specimen from different groups. Constipation mice exhibited thicker muscle layers, higher levels of cytokines, including IL-17 and IL-23, and lower content of IL-22. Bacterial abundance and diversity varied tremendously. Notably, the alterations were reversed following rhubarb extract treatment. Additionally, Constipation also had a substantial impact on short-chain fatty acids (SCFAs), medium- and long-chain fatty acids (MLCFAs), and the expression of SCFA receptors, GPR41 and GPR43. This thesis has provided insight that rhubarb extract promoted the flexibility of collagen fiber, reduced pro-inflammatory cytokines, enhanced anti-inflammatory cytokines, and maintained gut microflora balance with potential impacts on the fatty acid and polyamine metabolism.
PubMed: 36545319
DOI: 10.3389/fphar.2022.1048134 -
Journal of Biosciences 2021Slow transit constipation (STC) is a gastrointestinal disorder characterized by abnormal prolonged colonic transit time, which affects the life quality of many people....
Slow transit constipation (STC) is a gastrointestinal disorder characterized by abnormal prolonged colonic transit time, which affects the life quality of many people. The decrease number of interstitial cells of Cajal (ICCs) is involved in the pathogenesis of STC. However, the molecular mechanism of loss of ICCs in STC remains unclear, making it difficult to develop new agents for the disease. In this study, we investigated the mechanism of decreasing ICCs in the pathogenesis of STC. We constructed the STC model rats by using atropine and diphenoxylate. A series of methods were used including immunofluorescence and immunochemistry staining, western blot, qRT-PCR, exosomes extraction and exosomes labeling. The results indicate that ICCs decreased in the STC rats accompanied with the macrophages activation. Further studies suggested that macrophages decreased the cell viability of ICCs by secretion exosomes containing miR-34c-5p. miR-34c5p targeted the 3Ꞌ -UTR of stem cell factor(SCF) mRNA and regulated the expression of SCF negatively. In conclusion, we demonstrated a novel regulatory mechanism of ICCs cell viability in STC. We found that exosome miR-34c-5p mediate macrophage-ICCs cross-talk. M1 macrophages derived exosomes miR-34c-5p decreased ICCs cell viability by directly targeting SCF.
Topics: Analgesics, Opioid; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Atropine; Cell Survival; Constipation; Diphenoxylate; Exosomes; Gastrointestinal Motility; Gene Expression Regulation; Interstitial Cells of Cajal; Macrophages; MicroRNAs; Muscarinic Antagonists; Proto-Oncogene Proteins c-kit; RNA, Messenger; Rats; Rats, Sprague-Dawley; Stem Cell Factor
PubMed: 34544909
DOI: No ID Found -
Drug Design, Development and Therapy 2021The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan...
AIM
The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan pastoralists, is very different from other kinds of sour milk, and the microorganisms it contains are special. subsp. HFY14 (LLSL-HFY14) is a new lactic acid bacterium isolated from naturally fermented yak yogurt. The purpose of this study was to study the inhibitory effect of the bacterium on constipation.
METHODS
Constipation was induced in ICR mice with diphenoxylate, and the constipated mice were treated with LLSL-HFY14. The weight and feces of the mice were visually detected. Colonic tissues were observed on hematoxylin and eosin-stained sections. Serum indices were detected with kits. mRNA expression in the colon was determined by quantitative polymerase chain reaction assay.
RESULTS
Constipation caused weight loss, the number of defecation granules, defecation weight, fecal water content decreased, and the first black stool excretion time increased. LLSL-HFY14 alleviated these symptoms, and the effects were similar to those of lactulose (drug). The pathological examination revealed that constipation caused pathological changes in the colon, and LLSL-HFY14 effectively alleviated the disease. LLSL-HFY14 increased serum levels of motilin, gastrin, endothelin, substance P, acetylcholinesterase, and vasoactive intestinal peptide (VIP) and decreased serum levels of somatostatin in constipated mice. In addition, LLSL-HFY14 upregulated VIP, cAMP, protein kinase A, and aquaporin 3 expression in colonic tissues of constipated mice in a dose-dependent manner.
CONCLUSION
LLSL-HFY14 inhibited constipation, similar to lactulose, and has the potential to become a biological agent.
Topics: Animals; Aquaporin 3; Cattle; Constipation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diphenoxylate; Disease Models, Animal; Female; Lactococcus lactis; Mice; Mice, Inbred ICR; Probiotics; Signal Transduction; Somatostatin; Vasoactive Intestinal Peptide; Yogurt
PubMed: 34007157
DOI: 10.2147/DDDT.S309675 -
Antimicrobial Agents and Chemotherapy May 2024Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)....
Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The observed 50% effective concentrations ranged between 1.4 and 4.9 µM against the original wild-type strain and its variants. Time-of-addition experiments indicated that diphenoxylate is an entry blocker targeting a host factor involved in viral infection. Fluorescence microscopic analysis visualized that diphenoxylate prevented SARS-CoV-2 particles from penetrating the cell membrane and also impaired endo-lysosomal acidification. Diphenoxylate exhibited a synergistic inhibitory effect on SARS-CoV-2 infection in human lung epithelial Calu-3 cells when combined with a transmembrane serine protease 2 (TMPRSS2) inhibitor, nafamostat. This synergy suggested that efficient antiviral activity is achieved by blocking both TMPRSS2-mediated early and endosome-mediated late SARS-CoV-2 entry pathways. The antiviral efficacy of diphenoxylate against SARS-CoV-2 was reproducible in a human tonsil organoids system. In a transgenic mouse model expressing the obligate SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, intranasal administration of diphenoxylate (10 mg/kg/day) significantly reduced the viral RNA copy number in the lungs by 70% on day 3. This study underscores that diphenoxylate represents a promising core scaffold, warranting further exploration for chemical modifications aimed at developing a new class of clinically effective antiviral drugs against SARS-CoV-2.
PubMed: 38742905
DOI: 10.1128/aac.00341-24 -
British Medical Journal Feb 1980
Clinical Trial Comparative Study Randomized Controlled Trial
Topics: Chronic Disease; Clinical Trials as Topic; Codeine; Diarrhea; Diphenoxylate; Double-Blind Method; Humans; Isonipecotic Acids; Loperamide; Piperidines
PubMed: 6989434
DOI: 10.1136/bmj.280.6213.524 -
Foods (Basel, Switzerland) Mar 2019This study compares the prevention effects of Shuidouchi with different fermentation times on constipation in mice. Shuidouchi is a short-time fermented soybean product....
This study compares the prevention effects of Shuidouchi with different fermentation times on constipation in mice. Shuidouchi is a short-time fermented soybean product. By improving its processing technology, it can incur better biological activity and become a health food. The Shuidouchi-treated mice were evaluated using constipation-related kits, quantitative polymerase chain reaction (qPCR), and Western blot assays. After the mice were fed 72-h-fermented Shuidouchi (72-SDC) for 9 d, the defecation time to excrete the first black stool was lower than that of the control and 24-SDC and 48-SDC groups, but was much higher than that of the normal group. The gastrointestinal (GI) transit of the small intestine of the 72-SDC group was higher than that of the control and the 24-SDC and 48-SDC groups, but lower that of the normal group. Meanwhile, 72-SDC could significantly increase the levels of , endothelin-1 (ET-1), vasoactive intestinal peptide (VIP), and acetylcholinesterase (AchE) in the serum of constipated mice compared to the levels in mice in the control group. Moreover, 72-SDC could raise , stem cell factor (), glial cell-derived neurotrophic factor (), neuronal nitric oxide synthase (), and endothelial nitric oxide synthase () messenger RNA (mRNA) and protein expression levels, and reduce transient receptor potential cation channel subfamily V member 1 () and inducible nitric oxide synthase () expression levels in small-intestinal tissue compared to the levels in the control group. Meanwhile, 72-SDC also raised mRNA expression in gastric tissue and transient receptor potential ankyrin 1 () mRNA expression in colon tissue compared to the control group mice; these effects were stronger than those of 24-SDC and 48-SDC. Shuidouchi has good preventative effects on constipation and performs best when fermented for at least 72 h.
PubMed: 30832248
DOI: 10.3390/foods8030086 -
Cureus Apr 2023A high volume of ileostomy output in patients with extensive bowel resection can be hard to manage. This leads to extensive loss of fluids and electrolytes along with...
A high volume of ileostomy output in patients with extensive bowel resection can be hard to manage. This leads to extensive loss of fluids and electrolytes along with malabsorption. Medications have traditionally controlled it by delaying intestinal transit and decreasing intestinal and gastric secretion using opiates, loperamide, diphenoxylate, omeprazole, somatostatin, and octreotide. However, many patients depend on parenteral nutrition and fluid and electrolyte infusions, even with optimal drug therapy. Despite the best possible care, they may develop renal failure. Teduglutide is a glucagon-like peptide-2 (GLP-2) analog given as a daily subcutaneous injection, and it has been promising in managing short bowel syndrome. It has been effective in decreasing the dependence on parenteral nutrition. However, improving fluid and electrolyte balance can precipitate cardiac failure in some patients, especially those with borderline cardiac functions, hypertension, and thyroid disorders. This usually presents in the first few months of the initiation of teduglutide therapy and may require stopping the medication. We present the case report of an elderly female with a high-output stoma on parenteral nutrition on teduglutide. There was a significant decrease in stoma output, and parenteral nutritional support could be stopped. However, she presented with worsening dyspnea and was diagnosed with cardiac failure with an ejection fraction of 16%-20%. The baseline ejection fraction was 45%, done six months before this. Coronary angiography showed no stenosis in any vessels, and the decline in left ventricular ejection fraction and fluid overload was attributed to teduglutide therapy.
PubMed: 37197113
DOI: 10.7759/cureus.37518