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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 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Apr 2024To explore the therapeutic effect of transdermal patches containing Cassia seed extract applied at the navel on slow transit constipation (STC) in rats and explore the...
[Transdermal patches containing Cassia seed extract applied at the navel for slow transit constipation in rats: therapeutic effect and analysis of the spectrum-effect relationship].
OBJECTIVE
To explore the therapeutic effect of transdermal patches containing Cassia seed extract applied at the navel on slow transit constipation (STC) in rats and explore the spectrum-effect relationship of the patches.
METHOD
In a STC rat model established by gavage of compound diphenoxylate suspension for 14 days, the transdermal patches containing low, medium and high doses of Cassia seed extract (41.75, 125.25, and 375.75 mg/kg, respectively) were applied at the Shenque acupoint on the abdomen for 14 days after modeling, with constipation patches (13.33 mg/kg) as the positive control. After the treatment, fecal water content and intestinal propulsion rate of the rats were calculated, the pathological changes in the colon were observed with HE staining. Serum NO and NOS levels and the total protein content and NO, NOS and AChE expressions in the colon tissue were determined. HPLC fingerprints of the transdermal patches were established, and the spectrum-effect relationship between the common peaks of the patches and its therapeutic effect were analyzed.
RESULTS
Treatment with the transdermal patches containing Cassia seed extract significantly increased fecal water content and intestinal propulsion rate of the rat models, where no pathological changes in the colon tissue were detected. The treatment also suppressed the elevations of serum and colonic NO and NOS levels and reduction of AChE in STC rats. Twenty-eight common peaks were confirmed in the HPLC fingerprints of 6 batches of Cassia seed extract-containing patches. Analysis of the spectrum-effect relationship showed that autrantio-obtusin had the greatest contribution to the therapeutic effect of the patches in STC rats.
CONCLUSION
The Cassia seed extract-containing patches alleviates STC in rats via synergistic actions of multiple active ingredients in the extract, where autrantio-obtusin, rhein, chrysoobtusin, obtusin, obtusifolin, emodin, chrysophanol, and physcion are identified as the main active ingredients.
Topics: Animals; Rats; Cassia; Constipation; Seeds; Transdermal Patch; Plant Extracts; Rats, Sprague-Dawley; Colon; Acupuncture Points; Nitric Oxide; Disease Models, Animal; Male; Drugs, Chinese Herbal
PubMed: 38708506
DOI: 10.12122/j.issn.1673-4254.2024.04.14 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Apr 2024Following extended colon resections, it may not always be possible to perform colorectal anastomosis. The Deloyers procedure, which involves the transposition of the... (Review)
Review
Following extended colon resections, it may not always be possible to perform colorectal anastomosis. The Deloyers procedure, which involves the transposition of the right colon, has been identified as a viable solution. This report aims to discuss the circumstances under which the Deloyers procedure was performed, as well as to evaluate the early and late postoperative outcomes, by reviewing cases conducted between 2010 and 2023. In a 22-year-old female patient who suffered major organ and tissue loss (with injuries to the sigmoid colon, descending colon, transverse colon, and mesentery) due to a firearm injury, the Deloyers procedure was applied during restorative surgery following initial damage control surgery. The procedure involved mobilizing the cecum and right colon, performing a cranio-caudal rotation over the ileocolic artery pedicle, followed by an appendectomy, and creating a colorectal anastomosis using circular staplers. There were no complications during the postoperative follow-ups. By the 14th postoperative day, the patient was discharged and experienced bowel movements four times a day, managed with 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulfate. At the 6-month follow-up, the frequency of bowel movements had decreased to twice daily without the need for medical treatment. Given the functional outcomes in patients after extended left colectomies, the Deloyers procedure, with its low associated morbidity, stands out as a viable option.
Topics: Female; Humans; Young Adult; Adult; Firearms; Wounds, Gunshot; Anastomosis, Surgical; Colorectal Neoplasms
PubMed: 38634843
DOI: 10.14744/tjtes.2024.20813 -
The Kaohsiung Journal of Medical... Jun 2024Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside...
Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside compound extracted from the dried root of Paeonia lactiflora, has been found to alleviate STC, but the mechanisms of its effect remain unclear. The present study aimed to investigate the effects and mechanisms of PF on intestinal fluid metabolism and visceral sensitization in rats with compound diphenoxylate-induced STC. Based on the evaluation of the laxative effect, the abdominal withdrawal reflex test, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry were used to detect the visceral sensitivity, fluid metabolism-related proteins, and acid-sensitive ion channel 3/extracellular signal-regulated kinase (ASIC3/ERK) pathway-related molecules. PF treatment not only attenuated compound diphenoxylate-induced constipation symptoms and colonic pathological damage in rats but also ameliorated colonic fluid metabolic disorders and visceral sensitization abnormalities, as manifested by increased colonic goblet cell counts and mucin2 protein expression, decreased aquaporin3 protein expression, improved abdominal withdrawal reflex scores, reduced visceral pain threshold, upregulated serum 5-hydroxytryptamine, and downregulated vasoactive intestinal peptide levels. Furthermore, PF activated the colonic ASIC3/ERK pathway in STC rats, and ASIC3 inhibition partially counteracted PF's modulatory effects on intestinal fluid and visceral sensation. In conclusion, PF alleviated impaired intestinal fluid metabolism and abnormal visceral sensitization in STC rats and thus relieved their symptoms through activation of the ASIC3/ERK pathway.
Topics: Animals; Glucosides; Monoterpenes; Acid Sensing Ion Channels; Constipation; Rats; Male; MAP Kinase Signaling System; Rats, Sprague-Dawley; Colon; Gastrointestinal Transit; Aquaporin 3; Serotonin; Visceral Pain
PubMed: 38634140
DOI: 10.1002/kjm2.12829 -
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 -
Experimental Biology and Medicine... Dec 2023In clinical trials, rhubarb extract (Rb) was demonstrated to efficiently alleviate constipation. We would like to find out the underlying mechanism of rhubarb relieving...
In clinical trials, rhubarb extract (Rb) was demonstrated to efficiently alleviate constipation. We would like to find out the underlying mechanism of rhubarb relieving constipation. However, there are few studies on the effects of rhubarb on colonic mucus secretion and constipation. The aim of this study was to investigate the effects of rhubarb on colonic mucus secretion and its underlying mechanism. The mice were randomly divided into four groups. Group I was the control group and Group II was the rhubarb control group, with Rb (24 g/kg body weight [b.w.]) administered through intragastric administration for three days. Group III mice were given diphenoxylate (20 mg/kg b.w.) for five days via gavage to induce constipation. Group IV received diphenoxylate lasting five days before undergoing Rb administration for three days. The condition of the colon was evaluated using an endoscope. Particularly, the diameter of blood vessels in the colonic mucosa expanded considerably in constipation mice along with diminishing mucus output, which was in line with the observation via scanning electron microscope (SEM) and transmission electron microscope (TEM). We also performed metagenomic analysis to reveal the microbiome related to mucin gene expression level referring to mucin secretion. In conclusion, Rb relieves constipation by rebuilding mucus homeostasis and regulating the microbiome.
Topics: Mice; Animals; Rheum; Diphenoxylate; Mucins; Constipation; Colon; Mucus; Homeostasis
PubMed: 38073524
DOI: 10.1177/15353702231211859 -
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 -
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