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.

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.

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.

Rotigotine-loaded microspheres exerts the antinociceptive effect via central dopaminergic system.

Rotigotine-loaded microspheres (RoMS), a sustained-release formulation with a continuous release of rotigotine for more than 7 days in vivo, have been conducted a clinical trial for the treatment of Parkinson's disease (PD). Previous work from our laboratory showed that RoMS exerted an antinociceptive effect in rat models of inflammatory pain. The purpose of this study was to investigate the mechanisms of action underlying the antinociceptive effect of RoMS. A rat model of inflammatory pain was prepared by an intraplantar injection of carrageenan. The hot plate test and the Randall-Selitto test were used to evaluate the effect of domperidone (selective D2 receptor antagonist), D2D3 shRNA, and naloxone (nonselective opioid receptor antagonist) on RoMS-mediated antinociceptive efficacy. The expressions of D2 and D3 receptors in the striatum and periaqueductal gray were measured by Western blotting. Intracerebroventricular injection of domperidone abated the antinociceptive effect of RoMS. However, intraperitoneal injection of domperidone had no significant effect on the antinociceptive action of RoMS. Intracerebroventricular injection with D2D3 shRNA significantly attenuated the expressions of D2 and D3 receptors in the striatum and the periaqueductal gray. D2 and D3 receptors silence significantly weakened RoMS-mediated antinociceptive effect. Intracerebroventricular injection of naloxone also alleviated the antinociceptive effect of RoMS. The results suggest that RoMS-mediated antinociceptive efficacy is associated with activating central dopamine D2 and D3 receptors. Opioid receptors play a role in the antinociceptive effect of RoMS.

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.

Simultaneous Determination of Celecoxib, Dezocine and Dexmedetomidine in Beagle Plasma Using UPLC-MS/MS Method and the Application in Pharmacokinetics.

BACKGROUND: An efficient, fast and sensitive ultra high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for simultaneous determination of celecoxib (CEL), dezocine (DEZ) and dexmedetomidine (DEX) in beagle plasma were established. METHODS: The beagle dogs plasmawas precipitated by acetonitrile. The column was Acquity UPLC BEH C18 column and the mobile phase was acetonitrile-formic acid with gradient mode, and the flow rate was set at 0.4 mL/min. Under the positive ion mode, CEL, DEZ, DEX and Midazolam (internal standard, IS) were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 381.10→282.10 for CEL, m/z 246.20→147.00 for DEZ, m/z 201.10→94.90 for DEX, and m/z 326.10→291.10 for IS. RESULTS: This UPLC-MS/MS method had good linearity for CEL, DEZ and DEX. The RSDs of inter-day and intra-day precision were the values of 0.31-7.66% and 0.11-9.63%, respectively; the RE values were from -6.05% to 10.98%. The extraction recovery was more than 79%, and the matrix effect was around 100%. The RSDs of stability were less than 8.96%. All of them met the acceptance standard of biological analysis method recommended by FDA. CONCLUSION: This UPLC-MS/MS method is an effective tool for the simultaneous determination of CEL, DEX and DEX, and has been successfully applied to the study of pharmacokinetics in beagle dogs.

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.

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.

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.

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.

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).

Rotigotine Transdermal Patch for Motor and Non-motor Parkinson's Disease: A Review of 12 Years' Clinical Experience.

Motor and non-motor symptoms (NMS) have a substantial effect on the health-related quality of life (QoL) of patients with Parkinson's disease (PD). Transdermal therapy has emerged as a time-tested practical treatment option, and the rotigotine patch has been used worldwide as an alternative to conventional oral treatment for PD. The efficacy of rotigotine on motor aspects of PD, as well as its safety and tolerability profile, are well-established, whereas its effects on a wide range of NMS have been described and studied but are not widely appreciated. In this review, we present our overall experience with rotigotine and its tolerability and make recommendations for its use in PD and restless legs syndrome, with a specific focus on NMS, underpinned by level 1-4 evidence. We believe that the effective use of the rotigotine transdermal patch can address motor symptoms and a wide range of NMS, improving health-related QoL for patients with PD. More specifically, the positive effects of rotigotine on non-motor fluctuations are also relevant. We also discuss the additional advantages of the transdermal application of rotigotine when oral therapy cannot be used, for instance in acute medical emergencies or nil-by-mouth or pre/post-surgical scenarios. We highlight evidence to support the use of rotigotine in selected cases (in addition to general use for motor benefit) in the context of personalised medicine.

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.

Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants.

Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.

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.

How to introduce a rotigotine patch to Parkinson's disease patients taking oral dopamine agonists.

OBJECTIVE: Ways of introducing a rotigotine patch to Parkinson disease (PD) patients include initial induction for dopamine agonist (DA)-free patients and overnight switch (OS), cross-titration (CT), and add-on (AO) for patients already taking oral DAs. We investigated whether or not the introductions method affects the continuation rate of rotigotine patch. METHODS: The subjects were 188 PD patients who started using a rotigotine patch at the Department of Neurology, Fukuoka University Hospital. The rate of successful continuation of rotigotine patch for one year after initiation and the reasons for discontinuation were investigated; for the patients who discontinued due to poor efficacy, the DA dose before and after the start of rotigotine patch treatment was determined. RESULTS: The 1-year continuation rates were 38.5 % (20/52) in the OS group, 61.5 % (8/13) in the CT group, 35.3 % (6/17) in the AO group, and 50.9 % (54/106) in the de novo group. The most common reason for discontinuation in all groups was skin reactions. Compared with the de novo group, only the OS group had a significantly higher discontinuation rate due to poor efficacy (3.8 % vs. 21.2 %, P <  0.001). However, in the OS group, the continuation rate in the subjects with an increased total DA dose, after rotigotine was introduced, was significantly higher than that in the subjects with a decreased total DA dose (p = 0.031). CONCLUSION: The use of a rotigotine patch with an equivalent dose should be considered when switching from oral DAs, and appropriate care should be administered for any skin reactions. The present findings suggested that not the introduction method but the use of an equivalent dose between DA formulations might affect the continuation rate of rotigotine patch.

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 reduces neuropathic pain behavior and glial activation through MT2 melatonin receptor modulation in a rat model of lysophosphatidylcholine-induced demyelination neuropathy.

In this study, we investigated whether melatonin treatment prevents development of neuropathic pain via suppression of glial mitogen-activated protein kinases (MAPKs) activation in the cuneate nucleus (CN) in a lysophosphatidylcholine (LPC)-induced median nerve demyelination neuropathy model. Rats were fed orally with melatonin once a day at a dose of 37.5, 75, or 150 mg/kg 30 min before until 3 days after LPC treatment. Subsequently, behavioral tests were conducted on these animals, and immunohistochemistry and immunoblotting were used for qualitative and quantitative analysis of glia and MAPKs, including ERK, JNK, and p38, activation. Enzyme-linked immunosorbent assays were applied to measure pro-inflammatory cytokine responses. Furthermore, intra-CN microinjection of S26131 (MT1 receptor antagonist), 4P-PDOT (MT2 receptor antagonist), or prazosin (MT3 receptor antagonist) were performed to investigate the association between melatonin receptor subtypes and effects of melatonin on demyelination neuropathy. LPC treatment of the median nerve induced a significant increase in glial fibrillary acidic protein (GFAP; an astrocyte marker) and ED1 (an activated microglia marker) immunoreactivity in the ipsilateral CN and led to development of neuropathic pain behavior. Inspection of GFAP-immunoreactive astrocytes revealed that astrocytic hypertrophy, but not proliferation, contributed to increased GFAP immunoreactivity. Double immunofluorescence showed that both GFAP-immunoreactive astrocytes and ED1-immunoreactive microglia co-expressed p-ERK, p-JNK, and p-p38 immunoreactivity. Melatonin administration dose-dependently reduced neuropathic pain behavior, decreased glial and MAPKs activation, and diminished the release of pro-inflammatory cytokines in the ipsilateral CN after LPC treatment. Furthermore, 4P-PDOT, but not S26131 or prazosin, antagonized the therapeutic effects of melatonin. In conclusion, administration of melatonin, via its cognate MT2 receptor, inhibited activation of glial MAPKs, production of pro-inflammatory cytokines, and development of demyelination-induced neuropathic pain behavior.