Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials.

OBJECTIVE: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause. METHODS: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test. RESULTS: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo ( P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred. CONCLUSIONS: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. METHODS: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II. DISCUSSION: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma. TRIAL REGISTRATION: Clinicaltrial.gov: NCT05064618 , registered on 1 October 2021. jRCT: jRCT2041210056 , registered on 27 August 2021.

Effects of Dezocine and Sufentanil on Th1/Th2 Balance in Breast Cancer Patients Undergoing Surgery.

BACKGROUND: It is very important for breast cancer patients undergoing surgery to choose an opioid that has little effect on the immune system. The aim of this study is to compare the effects of dezocine or sufentanil on postoperative pain and Th1/Th2 balance in patients undergoing breast cancer surgery. METHODS: Data from 92 breast cancer patients from January 2019 to July 2020 at Foshan Second People's Hospital (Guangdong, China) were analyzed. Sufentanil (SF) was used in group SF (n = 44) and dezocine (DE) in group DE (n = 48). The Visual Analog Scale (VAS) scores were assessed, and the percentages of Th1 cells and Th2 cells in peripheral blood were detected before anesthesia and at 2, 12, 24, and 48 hours after surgery. RESULTS: There was no significant difference in the VAS scores between the two groups at 2, 24, and 48 hours after surgery (P > 0.05). The VAS scores at 12 hours after surgery in group DE were significantly lower than those in group SF with a statistically significant difference (P < 0.05). The percentage of Th1 cells in group DE at 2, 12, 24, and 48 hours after surgery was significantly lower than that in group SF (P < 0.05). The percentage of Th2 cells in group DE at 2, 12, 24, and 48 hours after surgery was significantly lower than that in group SF (P < 0.05). The Th1/Th2 ratio at 2, 12, 24, and 48 hours after surgery was significantly higher in group DE than that in group SF (P < 0.05). CONCLUSION: Dezocine for anesthesia induction and postoperative analgesia can maintain the balance of Th1/Th2 more stable than, with the same analgesia efficacy as, sufentanil during the early postoperative period in breast cancer patients undergoing surgery.

Prolonged sub-lethal exposure to galaxolide (HHCB) and tonalide (AHTN) promotes the metastatic potential of glioblastoma tumor spheroids.

Galaxolide and tonalide are well-known polycyclic musks whose intensive use without limitations in numerous cleaning, hygiene, and personal care products has resulted in widespread direct human exposure via absorption, inhalation, and oral ingestion. Latest data shows that long-term, low-dose exposure to toxic chemicals can induce unpredictable harmful effects in a variety of living systems, however, interactions between synthetic musks and brain tumours remain largely unexplored. Glioblastoma (GB) accounts for nearly half of all tumours of the central nervous system and is characterized by very poor prognosis. The aims of this study were (1) to investigate the potential effect of long-term (20-generation) single and combined application of galaxolide and tonalide at sub-lethal doses (5-2.5 u M) on the angiogenesis, invasion, and migration of human U87 cells or tumour spheroids, and (2) to explore the underlying molecular mechanisms. Random amplified polymorphic DNA assays revealed significant DNA damage and increased total mutation load in galaxolide- and/or tonalide-treated U87 cells. In those same groups, we also detected remarkable tumour spheroid invasion and up-regulation of both HIF1-α/VEGF/MMP9 and IL6/JAK2/STAT3 signals, known to have important roles in hypoxia-related angiogenesis and/or proliferation. Prolonged musk treatment further altered angio-miRNA expression in a manner consistent with poor prognosis in GB. We also detected significant over-expression of the genes Slug, Snail, ZEB1, and Vimentin, which are biomarkers of epithelial to mesenchymal transition. In addition, matrigel, transwell, and wound healing assays clearly showed that long-term sub-lethal exposure to galaxolide and/or tonalide induced invasion and migration proposing a high metastatic potential. Our results suggest that assessing expression of HIF-1a, VEGF, STAT3, and the miR-17-92 cluster in biopsy samples of GB patients who have a history of possible long-term exposure to galaxolide or tonalide could be beneficial for deciding a therapy regime. Additionally, we recommend that extensively-used hygiene and cleaning materials be selected from synthetic musk-free products, especially when used in palliative care processes for GB patients.

Effects of dezocine on morphine tolerance and opioid receptor expression in a rat model of bone cancer pain.

BACKGROUND: Clinically, the coadministration of opioids to enhance antinociception and decrease tolerance has attracted increasing research attention. We investigated the effects of dezocine, a mu- and kappa-opioid receptor agonist/antagonist, on morphine tolerance and explored the involvement of opioid receptor expression in a rat model of bone cancer pain. METHODS: Thermal nociceptive thresholds were measured after the subcutaneous injection of morphine (10 mg/kg) alone or combined with dezocine (10 or 1 mg/kg) for 7 consecutive days. Real-time PCR and western blot analysis were used to examine opioid receptor expression in the periaqueductal gray (PAG) and spinal cord. RESULTS: The analgesic effect was significantly decreased after 4 days of morphine administration. We observed that low-dose dezocine significantly attenuated morphine tolerance without reducing the analgesic effect of morphine. Low-dose dezocine coadministration significantly reversed the downregulated expression of mu (MOR) and delta (DOR) opioid receptors in the PAG and the upregulated expression of kappa (KOR) and DOR in the spinal cord induced by morphine. Moreover, low-dose dezocine coadministered with morphine significantly inhibited KOR expression in both the PAG and spinal cord. CONCLUSIONS: The combination of low-dose dezocine with morphine may prevent or delay the development of morphine tolerance in a rat model of bone cancer pain. The regulation of opioid receptor expression in the PAG and spinal cord may be part of the mechanism.

In Vivo Induction of P-Glycoprotein Function can be Measured with [18F]MC225 and PET.

P-Glycoprotein (P-gp) is an efflux pump located at the blood-brain barrier (BBB) that contributes to the protection of the central nervous system by transporting neurotoxic compounds out of the brain. A decline in P-gp function has been related to the pathogenesis of neurodegenerative diseases. P-gp inducers can increase the P-gp function and are considered as potential candidates for the treatment of such disorders. The P-gp inducer MC111 increased P-gp expression and function in SW480 human colon adenocarcinoma and colo-320 cells, respectively. Our study aims to evaluate the P-gp inducing effect of MC111 in the whole brain in vivo, using the P-gp tracer [18F]MC225 and positron emission tomography (PET). Eighteen Wistar rats were treated with either vehicle solution, 4.5 mg/kg of MC111 (low-dose group), or 6 mg/kg of MC111 (high-dose group). Animals underwent a 60 min dynamic PET scan with arterial-blood sampling, 24 h after treatment with the inducer. Data were analyzed using the 1-tissue-compartment model and metabolite-corrected plasma as the input function. Model parameters such as the influx constant (K1) and volume of distribution (VT) were calculated, which reflect the in vivo P-gp function. P-gp and pregnane xenobiotic receptor (PXR) expression levels of the whole brain were assessed using western blot. The administration of MC111 decreased K1 and VT of [18F]MC225 in the whole brain and all of the selected brain regions. In the high-dose group, whole-brain K1 was decreased by 34% (K1-high-dose = 0.20 ± 0.02 vs K1-control = 0.30 ± 0.02; p < 0.001) and in the low-dose group by 7% (K1-low-dose = 0.28 ± 0.02 vs K1-control = 0.30 ± 0.02; p = 0.42) compared to controls. Whole-brain VT was decreased by 25% in the high-dose group (VT-high-dose = 5.92 ± 0.41 vs VT-control = 7.82 ± 0.38; p < 0.001) and by 6% in the low-dose group (VT-low-dose = 7.35 ± 0.38 vs VT-control = 7.82 ± 0.37; p = 0.38) compared to controls. k2 values did not vary after treatment. The treatment did not affect the metabolism of [18F]MC225. Western blot studies using the whole-brain tissue did not detect changes in the P-gp expression, however, preliminary results using isolated brain capillaries found an increasing trend up to 37% in treated rats. The decrease in K1 and VT values after treatment with the inducer indicates an increase in the P-gp functionality at the BBB of treated rats. Moreover, preliminary results using brain endothelial cells also sustained the increase in the P-gp expression. In conclusion, the results verify that MC111 induces P-gp expression and function at the BBB in rats. An increasing trend regarding the P-gp expression levels is found using western blot and an increased P-gp function is confirmed with [18F]MC225 and PET.

Lipopolysaccharide/D-galactosamine-induced acute liver injury could be attenuated by dopamine receptor agonist rotigotine via regulating NF-κB signaling pathway.

The pathological of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute liver injury is similar to what is seen clinically, and be mediated by the release of pro-inflammatory mediators. A growing body of studies have shown that dopamine (DA) and DA receptor agonist are associated with inflammation and immune response. Rotigotine, a non-ergoline dopamine receptor agonist, is a drug for the treatment of Parkinson's disease. Rotigotine-loaded microspheres (RoMS) is an intramuscular extended-release agent, which can steadily release rotigotine for more than 7 days after a single administration. The present study aimed to investigate the effects of rotigotine and RoMS on inflammation and acute liver injury induced by LPS/D-Gal in mice. The LPS/D-Gal-induced liver injury was evidenced by increases of serum aminotransferases activities and liver histological lesions. Pretreatment with rotigotine or RoMS not only ameliorated the liver histologic lesions, but also reduced the activities of serum aminotransferases and the production of TNF-α. It also showed that rotigotine and RoMS increased DA receptor 2 (DRD2) expression in LPS/D-Gal-exposed mice. Rotigotine and RoMS activated ß-arrestin 2, inhibited the phosphorylation of Akt, IκB and the transposition of NF-κB. In line with the above findings, the protective effects of rotigotine and RoMS were abrogated by haloperidol, a DA receptor antagonist. In conclusion, dopamine receptor agonist can regulate NF-κB inflammatory signaling pathway and exert protective effects in LPS/D-Gal-induced liver injury.

Effect of Dezocine on the Ratio of Th1/Th2 Cytokines in Patients Receiving Postoperative Analgesia Following Laparoscopic Radical Gastrectomy: A Prospective Randomised Study.

PURPOSE: To evaluate the effect of dezocine on the postoperative ratio of Th1/Th2 cytokines in patients undergoing laparoscopic radical gastrectomy. PATIENTS AND METHODS: Sixty patients undergoing laparoscopic radical gastrectomy were randomly divided into two groups (n=30): dezocine group (Group D) and sufentanil group (Group S). They received patient-controlled intravenous analgesia (PCIA) after the operation with either dezocine 0.8 mg/kg (Group D) or sufentanil 2 µg/kg (Group S). Both groups also received ondansetron 8 mg diluted to 100 mL with saline. The primary outcome was the Th1/Th2 cytokines ratio at predetermined intervals, 30 min before the induction of general anaesthesia and 0, 12, 24 and 48 h after surgery. The secondary endpoints were patients' pain scores, measured on a visual analogue scale (VAS) at predetermined intervals (0, 12, 24 and 48 h after surgery), and side effects at follow-up 48 h after surgery. RESULTS: The Th1/Th2 cytokines ratio in Group D was significantly higher than Group S (P<0.05) 12, 24 and 48 h after the operation. There were no significant differences in VAS pain scores between groups at 0, 12, 24 and 48 h after surgery (P>0.05). Compared to Group S, the incidence of postoperative nausea, vomiting and lethargy was significantly lower in Group D (P<0.05). CONCLUSION: Dezocine increases the ratio of Th1/Th2 cytokines, relieves postoperative pain and causes fewer side effects in patients undergoing laparoscopic radical gastrectomy.

Phase I study of tamibarotene monotherapy in pediatric and young adult patients with recurrent/refractory solid tumors.

PURPOSE: Tamibarotene is a synthetic retinoid that inhibits proliferation and induces differentiation of malignant cells by binding to the retinoic acid receptor α/ß. Previous in vitro studies have shown that some pediatric solid tumors with retinoic acid receptors differentiate in response to retinoic acid. We conducted a phase I dose-escalation study to determine the recommended dose of tamibarotene for further study in pediatric and young adult patients with recurrent/refractory solid tumors. METHODS: Pediatric and young adult patients with recurrent/refractory solid tumors were administered tamibarotene at 4, 6, 8, 10, and 12 mg/m2/day for 14 or 21 days of a 28 day cycle. Safety, efficacy, and pharmacokinetics of tamibarotene were evaluated. RESULTS: Twenty-two patients (median age 8 years) were enrolled in this study. No dose-limiting toxicity (DLT) was encountered, and tamibarotene was generally well tolerated. Two patients experienced severe adverse events (AEs), leading to discontinuation of the treatment. One grade 4 venous thrombosis and one grade 2 erythema multiforme were observed, which promptly resolved after tamibarotene discontinuance. The grade 4 venous thrombosis was a severe AE but not DLT because it occurred after the evaluation period. Pharmacokinetic analyses showed a dose-dependent increase in the maximum drug concentration (Cmax) and area under the concentration-time curve (AUC). None of the patients achieved a complete response or partial response. Seven patients had stable disease lasting longer than 18 weeks. CONCLUSIONS: The recommended dose for phase II study of tamibarotene in pediatric and young adult patients with refractory solid tumors is 12 mg/m2/day for 21 days in a 28 day cycle.

Analgesic comparison of dezocine plus propofol versus fentanyl plus propofol for gastrointestinal endoscopy: A meta-analysis.

INTRODUCTION: As the adjunctive anesthesia to propofol, both dezocine and fentanyl showed some potential for gastrointestinal endoscopy. This meta-analysis aimed to compare their efficacy and safety. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of dezocine versus fentanyl for the anesthesia of patients undergoing gastrointestinal endoscopy were included. RESULTS: Five RCTs involving 677 patients were included in the meta-analysis. Overall, compared with fentanyl plus propofol for gastrointestinal endoscopy, dezocine plus propofol resulted in the reduction in propofol dose(mean difference [MD] = -11.72; 95% confidence interval [CI] = -22.83 to -0.61; P = .04), awakening time (std. MD = -1.79; 95% CI = -3.31 to -0.27; P = .02) and hypopnea (risk ratio [RR] = 0.16; 95% CI = 0.06-0.41; P = .0002), but had no remarkable effect on induction time (MD = 1.20; 95% CI = -0.98 to 3.39; P = .28), postoperative pain score (MD = -0.38; 95% CI = -1.00 to 0.24; P = .24), nausea or vomiting (RR = 0.45; 95% CI = 0.10-1.98; P = .29). CONCLUSION: Dezocine plus propofol may be better for the anesthesia of gastrointestinal endoscopy than fentanyl plus propofol.

Dexmedetomidine combined with sufentanil and dezocine-based patient-controlled intravenous analgesia increases female patients' global satisfaction degree after thoracoscopic surgery.

BACKGROUND: There are no studies on the use of dexmedetomidine combined with sufentanil and dezocine-based patient-controlled intravenous analgesia (PCIA) in females undergoing thoracic surgery. We postulate that introducing dexmedetomidine to a combination of dezocine-based PCA drugs and sufentanil will increase female patients' global satisfaction degree. METHODS: One hundred fifty-two female patients with physical classification type I or II according to the American Society of Anesthesiologists undergoing thoracoscopic surgery were arbitrarily classified into two categories, either receiving sufentanil and dezocine-based PCIA (group C) or incorporating dexmedetomidine with sufentanil and dezocine-based PCIA (group D). The patients' global satisfaction degree, postoperative nausea and vomiting (PONV), PCA bolus, rescue analgesia requirements, drug-related adverse effects, rest and coughing visual analogue scale (VAS) ratings, and Ramsay sedation scores (RSS) were measured at 6, 12, 24, 36 and 48 h after surgery. RESULTS: Compared with the C group, the patient satisfaction degree was significantly higher; pain scores at rest and coughing were significantly different at 6, 12, 24, 36 and 48 h postoperatively; less rescue analgesia and PCA bolus were required; and a lower incidence of PONV was found in the D group. There were non-significant trends for the sedation scores and drug-related adverse effects in both groups. CONCLUSIONS: Dexmedetomidine combined with sufentanil and dezocine increased female patients' global satisfaction degree after thoracoscopic surgery. This effect could be linked to the improvement in postoperative analgesia and reduction in postoperative nausea and vomiting; the combined treatment did not increase drug-related adverse effects in female patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry number, ChiCTR2000030429 . Registered on March 1, 2020.

Belantamab mafodotin in combination with novel agents in relapsed/refractory multiple myeloma: DREAMM-5 study design.

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

PKC- and PKA-dependent phosphorylation modulates TREK-1 function in naïve and neuropathic rats.

PKC and PKA phosphorylation inhibit TREK-1 channels downstream of Gs protein-coupled receptor activation in vitro. However, the role of phosphorylation of TREK-1 in neuropathic pain is unknown. The purpose of this study was to investigate whether altered TREK-1 channel function by PKA and PKC modulators contributes to antiallodynia in neuropathic rats. Furthermore, we investigated if the in vitro described sites for PKC and PKA phosphorylation (S300 and S333, respectively) participate in the modulation of TREK-1 in naïve and neuropathic rats. L5/L6 spinal nerve ligation (SNL) induced tactile allodynia. Intrathecal injection of BL-1249 (TREK-1 activator) reversed nerve injury-induced tactile allodynia, whereas spadin (TREK-1 blocker) produced tactile allodynia in naïve rats and reversed the antiallodynic effect induced by BL-1249 in neuropathic rats. Intrathecal administration of rottlerin or Rp-cAMPs (PKC and PKA inhibitors, respectively) enhanced the antiallodynia observed with BL-1249 in neuropathic rats. In contrast, pretreatment with PdBu or forskolin (PKC and PKA activators, respectively) reduced the BL-1249-induced antiallodynia. Intrathecal injection of two high-activity TREK-1 recombinant channels, using a in vivo transfection method with lipofectamine, with mutations at PKC/PKA phosphosites (S300A and S333A) reversed tactile allodynia in neuropathic rats, with no effect in naïve rats. In contrast, transfection of two low-activity TREK-1 recombinant channels with phosphomimetic mutations at those sites (S300D and S333D) produced tactile allodynia in naïve rats and interfered with antiallodynic effects of rottlerin/BL-1249 or Rp-cAMPs/BL-1249. Data suggest that TREK-1 channel activity can be dynamically tuned in vivo by PKC/PKA to provoke allodynia and modulate its antiallodynic role in neuropathic pain.

Interaction of Analgesic Effects of Dezocine and Sufentanil for Relief of Postoperative Pain: A Pilot Study.

PURPOSE: The combination of dezocine and sufentanil is often used for postoperative analgesia in China and other areas, but the interaction of both two drugs is still unclear. The purpose of this study was to evaluate the interaction of the analgesic effects of dezocine and sufentanil in the patients after gynecological laparoscopic surgery. PATIENTS AND METHODS: We conducted a prospective, randomized, double-blinded clinical trial. A total of 150 patients were divided into 5 groups (30 in each group) in the post-anesthesia care unit, namely, dezocine group (Group D), sufentanil group (Group S) and dezocine mixed sufentanil groups (Group DS1-3). In group D and S, the initial dose of dezocine or sufentanil was 5mg and 5µg intravenously, respectively. In Group DS1, the initial dose was dezocine 5mg × 3/4 and sufentanil 5µg × 1/4. In Group DS2, the initial dose was dezocine 5mg × 1/2 and sufentanil 5µg × 1/2. In Group DS3, the initial dose was dezocine 5mg × 1/4 and sufentanil 5µg × 3/4. RESULTS: The median effective dose (ED50) of dezocine and sufentanil alone was 3.92 (95% confidence interval (CI) 3.01~4.64) mg and 3.71 (95% CI 2.78~4.39) µg, respectively. The isobolographic analysis showed that the combination of dezocine and sufentanil at 1:3, 1:1 or 3:1 appeared in the additive line. CONCLUSION: In conclusion, when simultaneously administered intravenously, combined dezocine and sufentanil produce an additive effect for relieving the acute nociception after gynecological laparoscopic surgery.

A small dose of dezocine suppresses remifentanil-induced cough in general anesthesia induction: a prospective, randomized, controlled study.

BACKGROUND: The aim of this prospective randomized controlled study was to evaluate whether pretreatment with a small dose of dezocine could prevent remifentanil-induced cough in general anesthesia induction. TRIAL DESIGN: a prospective, randomized, controlled study. METHODS: A total of 210 patients receiving elective operative hysteroscopy from December 2018 to April 2019 were enrolled in the present study. They were randomly equally separated into dezocine group (n = 105) and control group (n = 105). Patients were intravenously pre-administrated with dezocine 0.03 mg/kg (diluted to 5 mL) or the same volume of normal saline 1 min prior to remifentanil infusion. One minute later, intravenous injection of propofol 1.5 mg/kg and cisatracurium 0.1 mg/kg were given to all patients for induction of general anesthesia. The counts of coughs occurred during the anesthesia induction period were recorded and the severity of cough was scaled. RESULTS: There were 7 cases of mild cough in dezocine group and 18 cases of mild cough, 12 cases of moderate cough and 4 cases of severe cough in control group. The incidence rate of cough was significantly lower and the severity of cough was obviously relieved in dezocine group compared to control group (6.67% vs. 32.38%, P <  0.001). The two groups were not significantly different in heart rate and mean arterial pressure before the induction, before and after the intubation, and in operating time and postoperative visual analog scale pain scores. CONCLUSION: This study recommends the efficacy and safety of a pretreatment with a small dose of dezocine in reducing remifentanil-induced cough during general anesthesia. TRIAL REGISTRATION: ChiCTR2000032035 . Date of registration: Retrospectively registered on 2020/04/18.

Melatonin stimulates VEGF expression in human granulosa-lutein cells: A potential mechanism for the pathogenesis of ovarian hyperstimulation syndrome.

Melatonin can be synthesized and secreted not only by the pineal gland but also by many extra-pineal tissues. It has been shown that many ovarian functions are regulated by melatonin locally. Ovarian hyperstimulation syndrome (OHSS) is a serious complication during ovulation induction of the in vitro fertilization treatment. To date, the etiology of OHSS is not fully understood. However, vascular endothelial growth factor (VEGF) is recognized as a critical mediator for the pathogenesis of OHSS. High expression of melatonin has been detected in the follicular fluid of OHSS patients. However, whether VEGF expression can be regulated by melatonin in human granulosa cells and further contributes to the pathogenesis of OHSS remain unknown. In this study, we show that melatonin stimulates VEGF expression in human granulosa-lutein (hGL) cells. Our results reveal that the MT2 receptor and activation of AKT are involved in melatonin-induced VEGF expression. Using a rat OHSS model, we report that the VEGF levels are up-regulated in the ovaries of OHSS rats. Blocking the melatonin system by administrating MT2 receptor antagonist, 4-P-PDOT, alleviates OHSS symptoms by decreasing the expression of VEGF. In addition, the expression levels of melatonin and VEGF in the follicular fluid of OHSS patients are up-regulated and positively correlated. This study demonstrates an important role for melatonin in regulating the pathogenesis of OHSS.

Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women.

BACKGROUND AND OBJECTIVES: Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. METHODS: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose. RESULTS: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract. CONCLUSIONS: These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile.

Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial.

BACKGROUND: Postoperative depression is one of the most common mental disorders in patients undergoing cancer surgery and it often delays postoperative recovery. We investigated whether dezocine, an analgesic with inhibitory effect on the serotonin and norepinephrine reuptake, could relieve postoperative depressive symptoms in patients undergoing colorectal cancer surgery. METHODS: This randomized, controlled, single-center, double-blind trial was performed in the Second Affiliated Hospital of the Army Medical University. A total of 120 patients were randomly assigned to receive either sufentanil (1.3 µg/kg) with dezocine (1 mg/kg) (dezocine group; n = 60) or only sufentanil (2.3 µg/kg) (control group; n = 60) for patient-controlled intravenous analgesia after colorectal cancer surgery. The primary outcome was the Beck Depression Inventory score at 2 days after surgery. The secondary outcomes included the Beck Anxiety Inventory, sleep quality, and quality of recovery scores. RESULTS: Compared with those in the control group, patients in the dezocine group had lower depression scores (7.3±3.4 vs. 9.9±3.5, mean difference 2.6, 95% CI: 1.4-3.9; P<0.001) at 2 days after surgery and better night sleep quality at the day of surgery (P = 0.010) and at 1 day after the surgery (P<0.001). No significant difference was found in other outcomes between the two groups. CONCLUSIONS: Intravenous analgesia using dezocine can relieve postoperative depression symptoms and improve sleep quality in patients undergoing colorectal cancer surgery.

Nose to brain delivery of rotigotine loaded chitosan nanoparticles in human SH-SY5Y neuroblastoma cells and animal model of Parkinson's disease.

Rotigotine, a non-ergoline dopamine agonist, has been shown to be highly effective for the treatment of Parkinson's disease (PD). However, despite its therapeutic potential, its' clinical applications were hindered due to low aqueous solubility, first-pass metabolism and low bioavailability. Therefore, we developed rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery and evaluated its neuronal uptake, antioxidant and neuroprotective effects using cell-based studies. The pharmacological effects of nose-to-brain delivery of the RNPs were also evaluated in an animal model of PD. The average particle size, particle size distribution and entrapment efficiency of the RNPs were found to be satisfactory. Exposure of RNPs for 24 h did not show any cytotoxicity towards SH-SY5Y human neuroblastoma cells. Furthermore, the RNPs caused a decrease in alpha-synuclein (SNCA) and an increase in tyrosine hydroxylase (TH) expression in these cells, suggestion that the exposure alleviated some of the direct neurotoxic effects of 6-OHDA. Behavioral and biochemical testing of RNPs in haloperidol-induced PD rats showed a reversal of catalepsy, akinesia and restoration of swimming ability. A decrease in lactate dehydrogenase (LDH) and an increase in catalase activities were also observed in the brain tissues. The results from the animal model of PD show that intranasally-administered RNPs enhanced brain targeting efficiency and drug bioavailability. Thus, RNPs for nose-to-brain delivery has significant potential to be developed as a treatment approach for PD.

The application of dexmedetomidine combined with dezocine in thoracoscopic radical resection of lung cancer and its effect on awakening quality of patients.

OBJECTIVE: The paper aims to explore the application of dexmedetomidine combined with dezocine in thoracoscopic radical resection of lung cancer and its effect on the awakening quality. PATIENTS AND METHODS: 122 patients undergoing thoracoscopic radical resection of lung cancer in The Affiliated Hospital of Qingdao University from April 2009 to January 2012 were selected as the subjects of the study. Among them, 68 patients were anesthetized with dexmedetomidine combined with dezocine as a study group, 54 patients with midazolam combined with fentanyl as a control group. The onset of anesthetic, operation time, awakening time, extubation time, and recovery time was compared. The mean arterial pressure (MAP), central venous pressure (CVP), and heart rate (HR) were compared before anesthesia (t0), at extubation (t1), 10 min after extubation (t2), and when patients left anesthesia recovery room (t3). The postoperative sedation score (Ramsay), modified the objective pain score (MOPS), and the pediatric anesthesia emergence delirium (PAED) score were compared at the time of the postoperative awakening (b1), 30 min after awakening (b2), 1 hour after awakening (b3), and 3 hours after awakening (b4). RESULTS: There was no significant difference in MAP, CVP, and HR between the study group and the control group at t0 (p > 0.05). The scores of PAED at b3 and b4 in the study group were lower than those in the control group (p < 0.05). CONCLUSIONS: The anesthesia effect of dexmedetomidine combined with dezocine in thoracoscopic radical resection of lung cancer is better and safer than other drugs, and it can produce good sedation and analgesic effect.