Effect of DA-9701, a Novel Prokinetic Agent, on Post-operative Ileus in Rats.
ABSTRACT: Post-operative ileus (POI) is a common complication of abdominal surgery. DA-9701, an extract of Pharbitis Semen and Corydalis Tuber, is a new prokinetic agent that also alleviates visceral pain. The aim of this study was to investigate whether DA-9701 can ameliorate POI in rats.A total of 32 rats were divided into 4 groups: no surgery/no medication (NSNM), no surgery/medication (NSM), surgery/no medication (SNM), and surgery/medication (SM). Gastrointestinal transit (GIT), which is assessed by migration of charcoal, and cumulative stool weight were measured at 24 hours after surgery.GIT was significantly more delayed in the SNM group than in the other groups (SNM vs NSNM, P < 0.001; SNM vs NSM, P < 0.001; SNM vs SM, P = 0.005). Cumulative stool weight in that group was also lower than in the no surgery groups (SNM vs NSNM, P = 0.007; SNM vs NSM, P = 0.033), and there was no significant difference between the SM group and the no surgery groups (SM vs NSM, P = 0.703; SM vs NSNM, P = 0.347).DA-9701 can ameliorate POI by reducing delayed GIT and improving defecation in a rat model of POI.
Project description:BACKGROUND/AIMS:The effect of proton pump inhibitors (PPI) in Asian functional dyspepsia (FD) patients has not been well established as in Westerncountries. DA-9701, a novel prokinetic agent, stimulates gastric emptying and modulates visceral hypersensitivity in vivo and in human studies. This study was conducted to compare the efficacy of DA-9701 with a conventional PPI in mono or combination therapy in patients with FD. METHODS:In this double-blind, randomized, non-inferiority trial, 389 patients diagnosed with FD using Rome III criteria were allocated among3 groups: 30-mg DA-9701 t.i.d (means 3 times a day), 40-mg pantoprazole, and 30-mg DA-9701 t.i.d + 40-mg pantoprazole. Theprimary efficacy end-point was a global assessment of the patient binary response or response on a 5-Likert scale after 4 weeks. RESULTS:The global symptomatic improvement was 60.5% in the DA-9701 group, 65.6% in the pantoprazole group, and 63.5% in the DA-9701 + pantoprazole group using a 5-Likert scale at week 4 with no significant difference among 3 groups (P = 0.685). Symptomimprovement measured by binary outcome was significantly achieved in each of the 3 groups, but not different among groups.Patients in all treatment groups reported significant improvement in the response rate and symptoms according to FD subtypes anddyspepsia-related quality of life (P < 0.001), but there were no significant differences among the 3 groups. CONCLUSIONS:DA-9701 improves global and individual symptoms and increases dyspepsia-specific quality of life in patients with FD. The efficacyof DA-9701 monotherapy is comparable with pantoprazole and there is no additive effect with combination of DA-9701 andpantoprazole in patients with FD.
Project description:Improving gastric accommodation and gastric emptying is an attractive physiological treatment target in patients with functional dyspepsia (FD). We evaluated the effect of DA-9701, a new drug for FD, on gastric motor function after a meal in healthy volunteers using magnetic resonance imaging (MRI).Forty healthy volunteers were randomly allocated to receive either DA-9701 or placebo. After 5 days of treatment, subjects underwent gastric MRI (60 min before and 15, 30, 45, 60, 90, and 120 min after a liquid test meal). Gastric volume was measured through 3-dimensional reconstruction from MRI data. We analyzed 4 outcome variables including changes in total gastric volume (TGV), proximal TGV, and proximal to distal TGV ratio after a meal and gastric emptying rates after adjusting values at the pre-test meal.Changes in TGV and proximal TGV after a meal did not differ between the DA-9701 and placebo groups (difference between groups -25.9 mL, 95% confidence interval [CI] -54.0 to 2.3 mL, P = 0.070 and -2.9 mL, 95% CI -30.3 to 24.5 mL, P = 0.832, respectively). However, pre-treatment with DA-9701 increased postprandial proximal to distal TGV ratio more than placebo (difference between groups 0.93, 95% CI 0.08 to 1.79, P = 0.034). In addition, pre-treatment with DA-9701 significantly increased gastric emptying as compared with placebo (mean difference between groups 3.41%, 95% CI 0.54% to 6.29%, P = 0.021, by mixed model for repeated measures).Our results suggested that DA-9701 enhances gastric emptying and does not significantly affect gastric accommodation in healthy volunteers. Further studies to confirm whether DA-9701 enhances these gastric motor functions in patients with FD are warranted.ClinicalTrials.gov NCT02091635.
Project description:OBJECTIVE:Though cigarette smoking (CS) is a well-known risk factor for ischemic stroke (IS), there is no data on how CS affects the blood transcriptome in IS patients. METHODS:We recruited IS-current smokers (IS-SM), IS-never smokers (IS-NSM), control-smokers (C-SM), and control-never smokers (C-NSM). mRNA expression was assessed on HTA-2.0 microarrays and unique as well as commonly expressed genes identified for IS-SM versus IS-NSM and C-SM versus C-NSM. RESULTS:One hundred and fifty-eight genes were differentially expressed in IS-SM versus IS-NSM; 100 genes were differentially expressed in C-SM versus C-NSM; and 10 genes were common to both IS-SM and C-SM (P < 0.01; |fold change| ≥ 1.2). Functional pathway analysis showed the 158 IS-SM-regulated genes were associated with T-cell receptor, cytokine-cytokine receptor, chemokine, adipocytokine, tight junction, Jak-STAT, ubiquitin-mediated proteolysis, and adherens junction signaling. IS-SM showed more altered genes and functional networks than C-SM. INTERPRETATION:We propose some of the 10 genes that are elevated in both IS-SM and C-SM (GRP15, LRRN3, CLDND1, ICOS, GCNT4, VPS13A, DAP3, SNORA54, HIST1H1D, and SCARNA6) might contribute to increased risk of stroke in current smokers, and some genes expressed by blood leukocytes and platelets after stroke in smokers might contribute to worse stroke outcomes that occur in smokers.
Project description:Postoperative ileus (POI) is a transient loss of coordinated peristalsis precipitated by surgery and exacerbated by opioid pain medication. Ileus causes a variety of symptoms including bloating, pain, nausea, and vomiting, but particularly delays tolerance of oral diet and liquids. Thus POI is a primary determinant of hospital stay after surgery. 'Fast-track' recovery protocols, opioid sparing analgesia, and laparoscopic surgery reduce but do not eliminate postoperative ileus. Alvimopan is a mu opioid receptor antagonist that blocks the effects of opioids on the intestine, while not interfering with their centrally mediated analgesic effect. Several large randomized clinical trials have demonstrated that alvimopan accelerates the return of gastrointestinal function after surgery and subsequent hospital discharge by approximately 20 hours after elective open segmental colectomy. However, it has not been tested in patients undergoing laparoscopic surgery and is less effective in patients receiving nonsteroidal anti-inflammatory agents in a narcotic sparing postoperative pain control regimen. Safety concerns seen with chronic low dose administration of alvimopan for opioid bowel dysfunction have not been noted with its acute use for POI.
Project description:Postoperative ileus (POI) is an important factor prolonging the length of hospital stay following colorectal surgery. We retrospectively explored whether there is a clinically relevant association between intraoperative hypothermia and POI in patients who underwent laparoscopic colorectal surgery for malignancy within the setting of an enhanced recovery after surgery (ERAS) program between April 2016 and January 2017 at our institution. In total, 637 patients were analyzed, of whom 122 (19.2%) developed clinically and radiologically diagnosed POI. Overall, 530 (83.2%) patients experienced intraoperative hypothermia. Although the mean lowest core temperature was lower in patients with POI than those without POI (35.3 ± 0.5°C vs. 35.5 ± 0.5°C, P = 0.004), the independence of intraoperative hypothermia was not confirmed based on multivariate logistic regression analysis. In addition to three variables (high age-adjusted Charlson comorbidity index score, long duration of surgery, high maximum pain score during the first 3 days postoperatively), cumulative dose of rescue opioids used during the first 3 days postoperatively was identified as an independent risk factor of POI (odds ratio = 1.027 for each 1-morphine equivalent [mg] increase, 95% confidence interval = 1.014-1.040, P <0.001). Patients with hypothermia showed significant delays in both progression to a soft diet and discharge from hospital. In conclusion, intraoperative hypothermia was not independently associated with POI within an ERAS pathway, in which items other than thermal measures might offset its negative impact on POI. However, as it was associated with delayed discharge from the hospital, intraoperative maintenance of normothermia is still needed.
Project description:Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD? CD27? non-switched memory (NSM) and IgD? CD27? switched memory (SM) B cells, not in IgD? CD27? naïve (N) cells. How this selectivity is achieved remains poorly understood. Here we show that purified N, NSM and SM cell preparations are equally transformable in vitro to lymphoblastoid cells lines (LCLs) that, despite upregulating the activation-induced cytidine deaminase (AID) enzyme necessary for Ig isotype switching and Ig gene hypermutation, still retain the surface Ig phenotype of their parental cells. However, both N- and NSM-derived lines remain inducible to Ig isotype switching by surrogate T cell signals. More importantly, IgH gene analysis of N cell infections revealed two features quite distinct from parallel mitogen-activated cultures. Firstly, following 4 weeks of EBV-driven polyclonal proliferation, individual clonotypes then become increasingly dominant; secondly, in around 35% cases these clonotypes carry Ig gene mutations which both resemble AID products and, when analysed in prospectively-harvested cultures, appear to have arisen by sequence diversification in vitro. Thus EBV infection per se can drive at least some naïve B cells to acquire Ig memory genotypes; furthermore, such cells are often favoured during an LCL's evolution to monoclonality. Extrapolating to viral infections in vivo, these findings could help to explain how EBV-infected cells become restricted to memory B cell subsets and why EBV-driven lymphoproliferative lesions, in primary infection and/or immunocompromised settings, so frequently involve clones with memory genotypes.
Project description:BACKGROUND:Lung cancer (LC) remains the deadliest form of cancer globally. While surgery remains the optimal treatment strategy for individuals with early-stage LC, what the metabolic consequences are of such surgical intervention remains uncertain. METHODS:Negative enrichment-fluorescence in situ hybridization (NE-FISH) was used in an effort to detect circulating tumor cells (CTCs) in pre- and post-surgery peripheral blood samples from 51 LC patients. In addition, targeted metabolomics analyses, multivariate statistical analyses, and pathway analyses were used to explore surgery-associated metabolic changes. RESULTS:LC patients had significantly higher CTC counts relative to healthy controls with 66.67% of LC patients having at least 1 detected CTC before surgery. CTC counts were associated with clinical outcomes following surgery. In a targeted metabolomics analysis, we detected 34 amino acids, 147 lipids, and 24 fatty acids. When comparing LC patients before and after surgery to control patients, metabolic shifts were detected via PLS-DA and pathway analysis. Further surgery-associated metabolic changes were identified when comparing LA (LC patients after surgery) and LB (LC patients before surgery) groups. We identified SM 42:4, Ser, Sar, Gln, and LPC 18:0 for inclusion in a biomarker panel for early-stage LC detection based upon an AUC of 0.965 (95% CI 0.900-1.000). This analysis revealed that SM 42:2, SM 35:1, PC (16:0/14:0), PC (14:0/16:1), Cer (d18:1/24:1), and SM 38:3 may offer diagnostic and prognostic benefits in LC. CONCLUSIONS:These findings suggest that CTC detection and plasma metabolite profiling may be an effective means of diagnosing early-stage LC and identifying patients at risk for disease recurrence.
Project description:Purpose:Multimodal analgesia is an essential component of an enhanced recovery pathway (ERP). An ERP that includes the use of single-injection intrathecal analgesia (IA) has been shown to decrease morbidity and cost and shorten length of stay (LOS). Limited data exist on safety, feasibility, and the optimal IA regimen. Our objective was to characterize the efficacy, safety, and feasibility of IA within an ERP in a cohort of colorectal surgical patients. Methods:We performed a retrospective review of all consecutive patients aged???18 years who underwent open or minimally invasive colorectal surgery from October 2012 to December 2013. All patients were enrolled in an institutional ERP that included the use of single-injection IA. Demographics, anesthetic management, efficacy (pain scores and opiate consumption), postoperative ileus (POI), adverse effects, and LOS are reported. Results:601 patients were identified. The majority received opioid-only IA (91%) rather than a multimodal regimen. Median LOS was 3 days. Overall rate of ileus was 16%. Median pain scores at 4, 8, 16, 24, and 48 hours were 3, 2, 3, 4, and 3, respectively. There was no difference in postoperative pain scores, LOS, or POI based on intrathecal medication or dose received. Overall, development of respiratory depression (0.2%) or pruritus (1.2%) was rare. One patient required blood patch for postdural headache. Conclusion:Intrathecal analgesia is safe, feasible, and efficacious in the setting of ERP for colorectal surgery. All regimens and doses achieved a short LOS, low pain scores, and a low incidence of POI. This trial is registered with Clinicaltrails.gov NCT03411109.
Project description:BACKGROUND: Primary ovarian insufficiency (POI) is heterogeneous disease defined by amenorrhea or premature depletion of ovarian follicles before the age of 40 years. The etiology of POI is still unclear. The purpose of this study is to evaluate whether women with POI have an elevated serum levels of autoimmunologic parameters. METHODS: The serum from peripheral blood samples which come from 96 POI patients and 100 age-matched health women were analyzed for a series of autoimmune antibodies using protein microarray. The antibodies to double-stranded DNA (ds-DNA), histone (HIS), nuclear ribonucleoprotein (RNP), Sjogren's syndrome A (SSA/Ro), Sjogren's syndrome B (SSB/La) and Smith antigen, Jo-1, scleroderma-associated antigen (Scl-70) and centromere (CEN), zona pellucid (ZP), adrenocortical antibodies (ACA),Rheumatoid factor (RF), glomerular basement membrane (GBM), proliferating cell nuclear antigen (PCNA), myeloperoxidase (MPO), proteinase 3 (PR3), thyroid microsomal antibody and antinuclear antibody (ANA)were analyzed. RESULTS: Among the 96 women with POI and 100 age-matched health controls, women with POI had significantly elevated circulation levels of Jo-1 and PR3 (p = 0.010 and p = 0.001) whereas circulation levels of ANAs, dsDNA, histone, RNP, Sm, Scl-70, SSA, SSB, CEN, ZP, ACA, RF, GBM, PCNA, MPO and TM antibodies were similar between the two groups. CONCLUSIONS: This study shows that the autoimmune antibodies JO-1 and PR3 were significantly higher in POI women group which suggested that these antibodies may have played special role in POI, but the evaluation of the exact pathways of them remains to be determined.
Project description:Background: Irresponsible self-medication is a problem for health systems in developing countries. We aimed to estimate the frequency of self-medication and associated factors in users of drugstores and pharmacies in Peru. Methods: We performed a secondary data analysis of the 2015 National Survey on User Satisfaction of Health Services (ENSUSALUD), a two-stage probabilistic sample of all regions of Peru. Non self-medication (NSM), responsible self-medication (RSM) and irresponsible self-medication (ISM) were defined as the outcome categories. Demographic, social, cultural and health system variables were included as covariates. We calculated relative prevalence ratios (RPR) with their 95% confidence intervals (95%CI) using crude and adjusted multinomial logistic regression models for complex samples with NSM as the referent category. Results: 2582 participants were included. The average age was 41.4 years and the frequencies of NSM, RSM and ISM were 25.2%, 23.8% and 51.0%; respectively. The factors associated with RSM were male gender (RPR: 1.35; 95%CI: 1.06-1.72), being between 40 and 59 years old (RPR: 0.53; 95%IC: 0.39-0.72), being 60 or older (RPR: 0.39; 95%IC: 0.25-0.59), not having health insurance (RPR: 1.89; 95%CI: 1.31-2.71) and living in the Highlands region (RPR: 2.27; 95%CI: 1.23-4.21). The factors associated with ISM were male gender (RPR: 1.41; 95%CI: 1.16-1.72), being between 40 and 59 years old (RPR: 0.68; 95%IC: 0.53-0.88), being 60 or older (RPR: 0.65; 95%IC: 0.48-0.88) and not having health insurance (RPR: 2.03; 95%CI: 1.46-2.83). Conclusion: Around half of the population practiced ISM, which was associated with demographic and health system factors. These outcomes are the preliminary evidence that could contribute to the development of health policies in Peru.