Clinical Trial Comparing Remimazolam with Propofol during Intravenous Anesthesia: A Prospective Randomised Clinical Trial.

BACKGROUND AND OBJECTIVE: Remimazolam is a water-soluble sedative-anesthetic with short-acting properties and less hemodynamic effects. Currently, it is primarily used for gastroenteroscopy sedation. The aim of this study is to investigate the effectiveness and safety of Remimazolam as an alternative intravenous anesthetic agent in surgical patients, in order to expand clinical options beyond Propofol. METHODS: Eighty patients aged 20-69 and classified as an American Society of Anesthesiologists physical status I-II were randomly assigned to either the Remimazolam group (RM group) or the Propofol group (PR group) for anesthesia induction and maintenance. Hemodynamics and Bispectral Index (BIS) were recorded before and after anesthesia, along with other relevant indices such as the time, to loss of consciousness (LoC), operation time, anesthesia time, awakening time, the number of cases of injection site pain. Additionally, the Ramsay sedation score, intraoperative awareness, dreaming, and postoperative adverse events were also assessed. RESULTS: After anesthesia, both groups experienced a significant decrease in blood pressure compared to baseline values, however, the reduction in blood pressure was less significant in the RM group than in the PR group (P<0.05). The heart rate of patients in the RM group remained relatively stable at all time points. There were significantly more cases of injection site pain and use of pressor or atropine during operation observed in the PR group compared to the RM group (P<0.05). There were no significant differences between the two groups in terms of time to loss of consciousness, anesthesia time, operation time, awakening time, and intraoperative awareness (P>0.05). However, at 5 and 30 minutes after awakening, the Ramsay sedation score was significantly better in the RM group compared to the PR group (P<0.05). CONCLUSION: When remimazolam is used for intravenous anesthesia induction and maintenance, it can achieve a favorable anesthetic effect while maintaining a relatively stable blood pressure and heart rate. Patients experience shorter awakening times (8.3±3.7 min), better awakening quality (5min Ramsay sedation score is 2 points ), and no intraoperative awareness. TRIAL REGISTRATION NUMBER: AF SOP/3.6-01/5.1.

Intravenous Administration of Hypertonic Glucose Solution to Prevent Dizziness in Patients Undergoing Gastrointestinal Endoscopy Under General Anesthesia: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: Dizziness is a common complication of gastrointestinal endoscopy under general anesthesia. Dizziness is primarily caused by a lack of energy and blood volume following fasting and water deprivation. Hypertonic glucose solution (HGS) is an intravenous energy replenishment, that increases blood volume due to its hyperosmotic characteristics and can be directly absorbed from blood circulation. This study aimed to HGS can prevent dizziness after gastrointestinal endoscopy. METHODS: This was a double-blind, randomized, controlled study. Eligible patients were randomly allocated into two groups based on the intravenous agent administered before gastrointestinal endoscopy: Group A, saline (0.9%; 20 mL); and group B, HGS (50%; 20 mL). Overall, 840 patients were included in the statistical analysis. The scores and incidence of dizziness were assessed. RESULTS: The dizziness score were higher in group A than in group B (1.92 ± 0.08 vs. 0.92 ± 0.06; p < 0.01). The incidence of mild dizziness and moderate-to-severe dizziness was significantly lower in group B than in group A (40.10% vs. 51.78% and 3.10% vs. 19.72%, respectively; p < 0.01). The incidence and score of dizziness were significantly lower in males than in females (30.81% vs. 51.82% and 0.64 ± 0.08 vs. 1.12 ± 0.08, respectively; p < 0.01) after pretreatment with HGS. CONCLUSION: Pretreatment with HGS effectively prevents dizziness after gastrointestinal endoscopy under general anesthesia. The mechanism of action is unclear but might be related to body energy replacement and an increase in blood volume following HGS administration.

Knockdown of CBX7 inhibits ferroptosis in rats with cerebral ischemia and improves cognitive dysfunction by activating the Nrf2/HO-1 pathway.

Iron-dependent lipid peroxidation-induced ferroptosis has been implicated in the pathogenesis of cerebral ischemia. Ischemia-reperfusion (I/R) contributes to cognitive dysfunction. Chromobox7 (CBX7) was upregulated in neural progenitor cells, followed by hypoxia and ischemia, and the suppression of CBX7 protected against renal and cerebral I/R injuries. However, the role of CBX7 in ferroptosis and cognitive dysfunction in rats with cerebral ischemia has not yet been reported. In our study, first, rats with cerebral I/R were established through middle cerebral artery occlusion (MCAO). Intracerebroventricular injection of shRNA targeting CBX7 (sh-CBX7) enhanced brain water content, and reduced neurological deficit scores and infarct size in rats post MCAO. Second, rats were subjected to 4 trials per day for 4 consecutive days in a Morris water maze. The time to find the platform in with 1 min was recorded as escape latency. On day 5, the platform was removed to conduct a spatial probe test. Rats were given 1 min to find the position of the platform, and the times for crossing the target within 1 min were recorded. Crossing the platform time is the time spent in each quadrant. Data from the Morris water maze showed that cognitive dysfunction in ischemic rats was ameliorated by the injection of sh-CBX7, which decreased the swimming distance and escape latency of ischemic rats, increased the times for crossing the target and platform in the maze. Moreover, injection of sh-CBX7 down-regulated levels of MDA and ROS, while it up-regulated SOD and GSH-Px to repress the oxidative stress. Third, knockdown of CBX7 in ischemic rats decreased the concentration of the ferric ions and the protein expression of transferrin receptor 1 (TFR1), but enhanced the solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), resulting in the inhibition of ferroptosis. Lastly, expressions of Nrf2, HO-1 and NAD(P)H:quinone oxidoreductase 1 (NQO1) were up-regulated in ischemic rats post sh-CBX7 injection. In conclusion, suppression of CBX7 attenuated I/R injury, improved cognitive dysfunction and inhibited ferroptosis through the activation of the Nrf2/HO-1 signaling pathway.

Gastroscopy sedation: clinical trial comparing propofol and sufentanil with or without remimazolam.

BACKGROUND: Propofol-sufentanil is often used in clinical anesthesia for patients undergoing sedative gastroscopy, but there are still adverse events such as longer recovery time, respiratory depression and higher doses of propofol etc. This study was to evaluate the sedative effect of remimazolam-propofol-sufentanil in sedative gastroscopy. METHODS: Patients who were going to have gastroscopy examination were randomly divided into two groups: group RM (remimazolam-propofol-sufentanil group) and group PR (propofol-sufentanil group). Patients of each group were anesthetized according to the corresponding anesthesia procedure, and all observation indices were recorded. RESULTS: In the RM group, there were only small and unsignificant changes in the values of SBP, HR, RR and SpO2 after anesthesia (P>0.05), while the values of SBP, HR, RR and SpO2 in the PR group at each time point after anesthesia were significantly lower than those at T0, and the values of SBP and RR at T2, T3 and T4 were also significantly lower than those at T1 (P<0.05). The dosage of propofol (38±9 mg) in the RM group was significantly less than that (115±15 mg) in the PR group, meanwhile the anesthesia time (8.4±1.6 min), awakening time (2.9±0.8 min), discharge time (6.7±3.1 min) of the RM group were also significantly shorter than those of the PR group (14.5±3.3, 8.7±1.9, 12.4±3.6 min) (P<0.05), but there was no statistical significance between the two groups in other indices (P>0.05). CONCLUSIONS: In clinical practice, remimazolam-propofol-sufentanil sedative scheme has more advantages than propofol-sufentanil sedative scheme.

Probiotic Therapy (BIO-THREE) Mitigates Intestinal Microbial Imbalance and Intestinal Damage Caused by Oxaliplatin.

Gastrointestinal mucositis associated with the use of chemotherapeutic drugs can seriously affect the quality of life of patients. In this study, a probiotic mixture, BIO-THREE, was used to alleviate intestinal damage caused by oxaliplatin in mice and human patients. Kunming mice were injected with 15 mg/kg of oxaliplatin twice, and BIO-THREE tablets were administered to mice for 12 days. Patients with gastric cancer undergoing oxaliplatin treatment took BIO-THREE tablets for 2 weeks. The changes in the composition of fecal microbiota both in patients and mice were analyzed using 16S rRNA high-throughput sequencing. In mice, oxaliplatin caused a drop in body weight and produced lesions in the liver and small intestines. Probiotic therapy successfully mitigated the damage caused by oxaliplatin to the intestinal tract, but it was not very effective for the liver damage and weight loss caused by oxaliplatin. The sequencing of the gut microflora indicated that oxaliplatin treatment increased the abundance of Bacteroidetes and decreased the abundance of Prevotella in mice. After taking probiotics, the feces of mice and human patients both had a higher abundance of Plovitella and a lower abundance of Bacteroides. The increase in Bacteroidetes and decrease in Prevotella in the gut community might be associated with oxaliplatin-induced intestinal damage. Probiotics appeared to be beneficial, decreasing intestinal damage by restoring the abundance of Bacteroidetes and Prevotella.

The combination therapy with esomeprazole and flupenthixol/melitracen in symptom improvement of erosive gastritis complicated with negative feelings compared with Esomeprazole alone.

The purpose of this study was to evaluate the co-prescription efficacy of esomeprazole and flupenthixol/melitracen relative to that of solitary esomeprazole on erosive gastritis complicated with negative feelings. 140 erosive gastritis patients complicated with negative feelings enrolled in the present study. Seventy cases in the control group took esomeprazole, and 70 cases in the observation group received esomeprazole plus flupenthixol/Melitracen, both for 4 weeks. We gastroscopically checked the clinical symptoms, mucosal erosion, PGE2 and MDA levels in gastric mucosa, anxiety, depression, and recurrence before and after treatment in the groups. After treatment, the observation group had lower scores of clinical symptoms, mucosal erosions, Hamilton Depression Rating Scale (HAMD), and Hamilton Depression Rating Scale (HAMA) than the control group (p<0.05); as well, the observation group showed higher PGE2 and lower MDA levels than the control group (p<0.05); during six months of follow-up (100% follow-up rate), 16 and 34 recurrent cases occurred, respectively, in the observation and control groups (p<0.05).  Co-prescription of esomeprazole and flupenthixol/melitracen improved the clinical symptoms and mucosal erosions, relieved negative feelings and reduced the recurrence rate. The efficacy of the co-prescription is higher than that of the solitary prescription.

Combining metabolic profiling of plasma and faeces as a fingerprint of insulin resistance in obesity.

BACKGROUND & AIMS: Insulin resistance (IR) is one of the main risk factor for type 2 diabetes mellitus (T2DM). Nevertheless, its underlying pathophysiology is not completely established because IR is triggered by a complex interconnection of numerous factors impairing metabolism, promoting metabolome changes. METHODS: We used a metabolomics approach to identify plasma and faecal metabolites related to IR and obesity. We explored a cohort of 44 subjects at baseline, with 30 of them followed two years thereafter in a longitudinal study after an hypocaloric diet in the obese subjects. RESULTS: In all individuals as a whole, 11 plasma metabolites positively associated with BMI (acetoacetate, creatinine, glycerol, glycerol of lipids, VLDL, fatty esters, myo-inositol, phenylalanine, threonine, tyrosine and valine) and one negatively (phosphocholine), with similar associations at baseline and follow-up. Four of these metabolites (myo-inositol, valine, acetoacetate and phosphocholine) remained significant within obese and non-obese groups. Thirteen faecal metabolites positively associated with BMI at baseline and one negatively (glutamine). However, these correlations did not remain significant at follow-up. The correlations were not always consistent at baseline and at follow-up and the metabolites that showed significant correlations were different for the obese group compared with the control group. The percent change in plasma Δethanolamine, Δglucose, Δuracil and Δhypoxanthine were positively associated with ΔBMI. The percent change in plasma Δphosphocholine and of faecal Δhydroxyphenylacetate, and Δ2-hydroxyphenylacetate were associated with ΔHOMA-IR in those patients that lost weight. Faecal branched chain amino acids (BCAAs) in faeces were associated with IR, following a similar pattern to that described for plasma BCAAs. Choline derivates had an opposite behaviour. CONCLUSIONS: The integration of plasma and faecal metabolites represents a valuable fingerprint that could help in the identification of patients at risk for IR and in the design of novel therapeutic strategies to prevent IR and the development of overt T2DM in the context of obesity. The results are coherent with diet having a much greater impact on faecal metabolomic profile than on plasma metabolome.

Gut remediation: a potential approach to reducing chromium accumulation using Lactobacillus plantarum TW1-1.

Some lactobacilli have protective effects against some heavy metals in mammals, but the underlying mechanism is not fully understood. To evaluate the remediation potency and the mechanism of Lactobacillus against chromium (Cr) in mice, Lactobacillus plantarum TW1-1 was orally administrated to Kunming mice for 7 weeks during exposure to 1 mM K2Cr2O7 in drinking water. Results showed that TW1-1 helped to decrease Cr accumulation in tissues and increase Cr excretion in feces, and may also attenuate alterations in oxidative stress and histopathological changes caused by Cr exposure. Moreover, the chromate reduction ability of fecal bacteria doubled after administration of TW1-1 upon Cr induction. MiSeq sequencing of fecal bacterial 16S rRNA genes revealed that the overall structures of gut microbiota was shifted by Cr exposure and partially restored by TW1-1. The abundances of 49 of the 79 operational taxonomic units altered by Cr were reversed by TW1-1. Based on these, we proposed a working model of TW1-1 against Cr: TW1-1 helps to remove Cr from the host and meanwhile acts as a regulator of gut microbiota, which aids in chromate reduction and provide protection against Cr. We call this process of remediation of heavy metal in the gut "gut remediation".

Synthesis, structure-activity relationships and preliminary mechanism of action of novel water-soluble 4-quinolone-3-carboxamides as antiproliferative agents.

A series of novel water-soluble 4-quinolone-3-carboxamides was prepared and evaluated as antiproliferative agents. Preliminary results indicated that most compounds tested in this study showed potent antiproliferative potencies against human tumor cell lines, and compound 8k was found to be the most potent antiproliferative agents with IC50 value of lower than 10 µM against nine human tumor cell lines. These results suggested that (1) the alkylamino side chain substituent was the advisable pharmacophoric group for the enhanced antiproliferative activities; (2) the length of the alkylamino side chain moiety also affected their antiproliferative potencies, and three methylene units were more favorable; (3) introducing arylated alkyl substituent into N1-position of quinolone facilitated antiproliferative activities of this class of compounds. Further investigations on mechanism of action of this class of compound demonstrated that the representative compound 8k could trigger p53/Bax-independent colorectal cancer cell apoptosis via inducing ROS accumulation.

Effects of human opiorphin on food intake and water intake in mice following central administration.

Human opiorphin plays an important pharmacological functions in rats or mice. The present study was performed to investigate effects and underlying mechanism of central injected opiorphin on food intake and water intake in mice. Intracerebroventricularly (i.c.v.) administered opiorphin (5-20µg/kg) dose-dependently suppressed food intake in fasted mice, but had no influence on food intake in freely feeding mice. The cumulative food intake was significantly decreased at 60min after injection of 10 and 20µg/kg opiorphin and the food intake was significantly reduced during the 20-60min period after treatment. Non-selected opiate receptor antagonist naloxone could fully block the inhibitory effect induced by opiorphin on cumulative food intake at 60min in fasted mice, suggesting that the anorexic effect of opiorphin was related to the opioid system. Moreover, the anorexic effect induced by opiorphin in fasted mice was also significantly inhibited by pretreatment with captopril or valsartan, which suggested that endogenous angiotensin may be involved in the response to opiorphin. Interestingly, the effect of opiorphin on water intake was increased in both fasted and freely feeding mice, which was completely blocked by captopril and valsartan. Furthermore, naloxone did not modify the effect of opiorphin on water intake. All together, the food and water intake effects of opiorphin may be due to the protection of the endogenous angiotensin and opioid peptides from degradation by NEP or APN.

Neurotoxicity of intrathecal injections of dexmedetomidine into the rat spinal dorsal horn.

To investigate the neurotoxicity of intrathecal injections of dexmedetomidine, Sprague-Dawley rats were intrathecally injected with dexmedetomidine at doses of 0.75, 1.50 and 3.00 µg/kg into the spinal dorsal horn. We found that c-Fos expression in the rat spinal dorsal horn peaked at 7 hours following the 3.00 µg/kg dexmedetomidine injection, while the levels of c-Fos expression following 0.75 and 1.50 µg/kg dexmedetomidine were similar to those in the spinal dorsal horn of normal rats. At 48 hours following administration, the level of c-Fos expression was similar to normal levels. In addition, the intrathecal injections of dexmedetomidine increased paw withdrawal mechanical thresholds and prolonged thermal tail flick latencies. These results indicate that dexmedetomidine has pronounced antinociceptive effects. However, dexmedetomidine appears to have neurotoxic effects in the spinal cord because it increased c-Fos expression in the spinal dorsal horn within 7 hours following administration.

Regulation of spinal neuroimmune responses by prolonged morphine treatment in a rat model of cancer induced bone pain.

Cancer induced bone pain (CIBP) is a major clinical problem. Although opioids remain the principal axis in drug therapies for CIBP, their sustained application is known to induce cellular and molecular adaptations including enhanced neuroimmune reactivity. This is generally characterized by glial activation and proinflammatory cytokine production which frequently results in pharmacological tolerance. This research was performed to investigate spinal neuroimmune responses after prolonged systemic morphine treatment in a rat model of CIBP. The model was established using a unilateral intra-tibia injection of Walker 256 mammary gland carcinoma cells. Subcutaneous morphine was repeatedly administered from postoperative days 14 to 19. Mechanical allodynia to von Frey filaments and ambulatory pain scores were recorded to investigate changes of nociceptive behaviors. Spinal glial activation was detected by immunohistochemistry and real-time PCR; the production of proinflammatory cytokines (IL-1beta and TNF-alpha) was examined through real-time PCR and ELISA. Results showed that chronic morphine use failed to elicit analgesic tolerance in the rat CIBP model. Moreover, the treatment had no significant influence on the activated spinal glia morphology, cell density and expression of special cytomembrane markers, whereas it significantly down-regulated the local proinflammatory cytokine production at the mRNA and protein level. Collectively, these data suggest that chronic morphine treatment in CIBP is not concomitant with pharmacological tolerance, at least partially because the treatment fails to amplify spinal neuroimmune responses.

Evaluation of side effects through selective ablation of the mu opioid receptor expressing descending nociceptive facilitatory neurons in the rostral ventromedial medulla with dermorphin-saporin.

Descending facilitation from the rostral ventromedial medulla (RVM) contributes to some pathological pain states. The intra-RVM microinjection with dermorphin-saporin could specifically abolish this facilitation in rodent models by selectively ablating the RVM neurons expressing mu opioid receptors. Thus, this targeted lesion may be an alternative mechanism-based approach for intractable pain. This research was performed to investigate potential side effects after a single intra-RVM application of dermorphin-saporin in rats. Results showed though some acute cardiovascular signs were observed with dermorphin-saporin, the treatment exhibited no long-lasting significant influence on some physiological functions for up to 3-month observation period, including normal sensory function, locomotor activity, ingestive behaviors, body weight, rectal temperature, respiratory rate, heart rate, systolic blood pressure, cardiac structure and function. Moreover, there were only mild microglial responses on day 7 post-microinjection, while no significant increase in the immunostaining of astrocytes and no noticeable up-regulation in the production of proinflammatory cytokines were detected in the RVM treated with dermorphin-saporin. Taken together, these data would suggest that this selective ablation of mu opioid receptor bearing descending facilitatory neurons in the RVM with dermorphin-saporin did not elicit the long-standing evident adverse toxicity in terms of some physiological parameters and neurochemical alterations we determined, plausibly providing us a safe and reliable approach to treat some intractable pain.

[Construction of rat constitutively active recombinant caspase-3 and investigation of its pro-apoptotic effect in vitro].

OBJECTIVE: To investigate the apoptosis induction effect by the rat recombinant caspase-3. METHODS: Reversed rat caspase-3 gene was gained by settling the small subunit prior to the large one through recombinant PCR, and cloned into the expression vector to transfect human 293T cells and rat immortalized neural progenitor cells. The expression and pro-apoptotic effect of recombinant caspase-3 was observed by the changes of morphology of the transfected cells through immunofluorescence and analyzed by Annexin V-FITC staining, Flowcytometry and MTT assay. RESULTS: The transfected cells presented obvious apoptosis as detected by immunofluorescence. MTT assay showed that the proliferation of recombinant caspase-3 transfected cells was significantly inhibited [(48.35 +/- 0.16)%, (44.61 +/- 0.15)%] (P < 0.05). Annexin V-FITC staining revealed that the percentage of apoptotic cells in the transfectants of recombinant caspase-3 gene was [(30.7 +/- 1.5)%, (16.0 +/- 1.0)%] (P < 0.05), which was much higher than that of control cells. CONCLUSIONS: Rat recombinant caspase-3 can be expressed and induce apoptosis effectively, and used safely both in vitro and in vivo. It can also cause neural cells to death.