Parkinson's disease: symptoms and medications at the end of life.

OBJECTIVES: People with Parkinson's disease (PwP) have a high palliative symptom burden throughout their disease course, equivalent to advanced malignancy. We aim to establish trends in symptom frequency and prescribing in the 72 hours prior to death for PwP. METHODS: Retrospective case note review of PwP who died between February 2019 and September 2020. RESULTS: 51 patients were included. 60.78% of patients (n=31) had agitation and 58.82% (n=30) had pain in the final 72 hours. Patients with cognitive impairment were 4.67 times more likely to experience agitation (p=0.035) compared with those without, with higher total midazolam doses (29.18 mg vs 11.4 mg, p=0.21). Terminal motor symptoms were recorded in three patients. 28.57% of patients received the recommended dose of rotigotine for dopaminergic therapy. CONCLUSIONS: PwP have a significant symptom burden at the end of life (EOL) with levels of terminal agitation at the higher end of those expected in the general population. There was a trend towards higher doses of sedation, rather than analgesia, in people with coexistent cognitive impairment.Terminal stiffness, despite being seldom documented in the literature, is an important although infrequent symptom.Rotigotine use at EOL remains commonplace and better understanding of its effect and dosing is required.

Transdermal Rotigotine at End-of-Life for Parkinson's Disease: Association With Measures of Distress.

BACKGROUND: End-of-life (EOL) care for Parkinson's disease (PD) can be challenging when oral medications are no longer tolerated. MEASURES: To assess EOL prescribing for people with PD (PWP), focusing on rotigotine dosing and proxy measures of distress: benzodiazepine and opioid use. INTERVENTION: A retrospective audit of patient records from PWP who died between January 2019 and May 2022 at the Royal Hobart Hospital (RHH), Australia, was conducted. Data was systematically collated on demographics, symptoms, levodopa equivalent daily dose (LEDD) and rotigotine, oral morphine equivalent (OME) and benzodiazepine doses in the last 72 hours of life . OUTCOMES: Pain (72%), respiratory secretions (66%) and agitation (66%) were the most documented EOL symptoms. 83% (n = 52) of PWP were eligible for rotigotine and, of those, 13% (n = 7) received the correct dose, 38% (n = 20) a lower dose, 12% (n = 6) a higher dose and 37% (n = 19) did not receive any. Rotigotine dose was positively associated with total (P = 0.016) and PRN (P = 0.037) benzodiazepine dose. LEDD was positively associated with total benzodiazepine (P = 0.018) and total OME dose (P = 0.046). Contraindicated dopamine antagonists were prescribed for 43% of PWP and administered in 31% of those cases. CONCLUSIONS: Rotigotine dose and admission LEDD were both associated with proxy measures of distress in the last 72 hours of life. This suggests cautious use of rotigotine at EOL. LEDD may help identify patients at risk of distress. Rates of inappropriate prescribing and symptom prevalence were high, indicating a need for further staff education to optimize the care of PWP.

Population pharmacokinetics of rotigotine extended-release microspheres for intramuscular injection in patients with early-stage Parkinson's disease.

AIMS: Rotigotine extended-release microspheres is a weekly intramuscular injection formulation to treat Parkinson's disease. This study aimed to develop a population pharmacokinetics (PK) model for rotigotine extended-release microspheres to investigate its PK ethnic differences. METHODS: Data for the study were obtained from three studies in China, Japan and the US. The population PK model was developed using the Phoenix NLME 8.3.5 software. Two parallel absorption models were created to include both zero- and first-order absorptions. The elimination phase was evaluated for one- and two-compartment linear models. Moreover, covariates including sex, body weight, body mass index, albumin, creatinine clearance and race were input into the model using a stepwise covariate method. RESULTS: We constructed a one-compartment linear model with the first parallel absorption model identified as the best-fitting model. Simulation results in patients with lighter body weight (45 kg) exhibited a 27% increase in Cmax,ss and a 31% increase in AUCtau,ss compared to those with median body weight (65 kg). Patients with heavier body weight (103 kg) showed a 27% decrease in Cmax,ss and a 29% decrease in AUCtau,ss compared to the median body weight group. Asian patients displayed only a 21% increase in Cmax,ss and a 6% increase in AUCtau,ss compared to non-Asian. While we could not fully conclude that race does not affect rotigotine exposure, dosage adjustments based on race were not deemed necessary. CONCLUSIONS: Exposure differences were mainly attributed to body weight, while dose adjustments were not needed for patients of different racial identities.

The novel function of bexarotene for neurological diseases.

Bexarotene, a retinoid X receptor (RXR) agonist, is approved by FDA to treat cutaneous T-cell lymphoma. However, it has also demonstrated promising therapeutic potential for neurological diseases such as stroke, traumatic brain injury, Parkinson's disease, and particularly Alzheimer's disease(AD). In AD, bexarotene inhibits the production and aggregation of amyloid ß (Aß), activates Liver X Receptor/RXR heterodimers to increase lipidated apolipoprotein E to remove Aß, mitigates the negative impact of Aß, regulates neuroinflammation, and ultimately improves cognitive function. For other neurological diseases, its mechanisms of action include inhibiting inflammatory responses, up-regulating microglial phagocytosis, and reducing misfolded protein aggregation, all of which aid in alleviating neurological damage. Here, we briefly discuss the characteristics, applications, and adverse effects of bexarotene, summarize its pharmacological mechanisms and therapeutic results in various neurological diseases, and elaborate on the problems encountered in preclinical research, with the aim of providing help for the further application of bexarotene in central nervous system diseases.

Impact of body mass index on the severity of bexarotene-associated hypertriglyceridemia: A post hoc analysis of an open-labeled clinical study of combined bexarotene and phototherapy in Japanese patients with cutaneous T-cell lymphoma.

Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m2 group) and overweight and obese (BMI ≥25 kg/m2 group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m2 group and 88.9% (8/9) in the BMI ≥25 kg/m2 group. The incidence of grade ≥3 hypertriglyceridemia (≥500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m2 group and 7/8 (87.5%) in the BMI ≥25 kg/m2 group (P < 0.001). Consequently, dose reduction in the BMI ≥25 kg/m2 group was larger than that in the BMI <25 kg/m2 group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (ρ = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m2 , the sensitivity and specificity for identifying grade ≥3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI ≥25 kg/m2 is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.

A meta-analysis evaluating effects of the rotigotine in Parkinson's disease, focusing on sleep disturbances and activities of daily living.

BACKGROUND: Rotigotine transdermal patch (TP) is a useful dopaminergic medication for Parkinson's disease (PD). This meta-analysis attempted to evaluate the effects of rotigotine TP on motor performance, activities of daily living (ADL) limitations, and sleep disturbances in patients with PD. METHODS: Only randomized controlled clinical trials (RCTs) with placebo design were included in this study. The clinical outcomes, evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS III), UPDRS-II, UPDRS Part II + III, Parkinson's Disease Sleep Scale (PDSS)-2, and adverse events (AEs) were evaluated. The Jadad scale was used to evaluate study quality. RESULTS: A total of 16 RCTs with 4682 patients with PD were enrolled in this study. We found that rotigotine TP significantly reduced the UPDRS-III, UPDRS-II, and UPDRS Part II + III scores, indicating that rotigotine TP led to a significant amelioration of movement symptoms and ADL limitations. Moreover, we found that rotigotine TP significantly reduced PDSS-2 scores, suggesting that rotigotine TP led to a remarkable improvement in sleep quality. Meanwhile, compared with the placebo group, patients taking rotigotine TP did not have added incidence of AEs. CONCLUSION: This study verified the efficacy and safety of rotigotine TP in treating PD. The findings of the present study provide compelling evidence concerning and insight into clinical usage of rotigotine TP. Future studies will focus on more non-motor symptoms affected by rotigotine TP.

Efficacy of dezocine on preventing opioid-induced cough during general anaesthesia induction: a PRISMA-compliant systematic review and meta-analysis.

OBJECTIVES: To systematically review the effects of dezocine (DZC) on the occurrence rate and severity of opioid-induced cough (OIC). DESIGN: Systematic review and meta-analysis DATA SOURCES: PubMed, Embase, Cochrane Library, Ovid, Web of Science as well as Chinese BioMedical Literature & Retrieval System, China National Knowledge Infrastructure, Wanfang and VIP Data were searched from 1978 to 31 December 2020. INCLUSION CRITERIA: All randomised controlled trials (RCTs) comparing DZC with placebo on the occurrence rate and severity of OIC. DATA ANALYSIS: All data were analysed by using RevMan V.5.3. Each outcome was tested for heterogeneity, and randomised-effects or fixed-effects model was used in the presence or absence of significant heterogeneity. RESULTS: Our search yielded 33 RCTs including 4442 patients, and 2521 patients were allocated into the DZC group and 1921 into the control group. Fentanyl was administrated in 1880 patients and sufentanil in 2562 patients during the induction of general anaesthesia. The meta-analysis demonstrated that DZC significantly reduced the occurrence rate of OIC induced by either fentanyl (8.8% vs 49.7%, OR=0.07, 95% CI 0.04 to 0.12, p<0.00001) or sufentanil (5.0% vs 41.5%, OR=0.07, 95% CI 0.04 to 0.12, p<0.00001). The meta-analysis also indicated that the occurrence rate of mild, moderate and severe OIC in the DZC group was remarkably lower than that of the control group (mild: 3.6% vs 13.6%, OR=0.19, 95% CI 0.14 to 0.25, p<0.00001; moderate: 2.0% vs 13.6%, OR=0.12, 95% CI 0.09 to 0.18, p<0.00001; severe: 1.0% vs 13.9%, OR=0.08, 95% CI 0.05 to 0.12, p<0.00001). Additionally, the current meta-analysis indicated that DZC pretreatment was not associated with increased occurrence rate of adverse effects (7.0% vs 4.2%, OR=2.34, 95% CI 0.60 to 9.14, p=0.22) except for dizziness (11.8% vs 0%, OR=8.06, 95% CI 1.40 to 46.35, p=0.02). CONCLUSION: This meta-analysis demonstrated that DZC significantly inhibited OIC and may be used to manage OIC. More high-quality RCTs are needed to complement the safety of DZC. PROSPERO REGISTRATION NUMBER: CRD42019141255.

Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis.

Drug resistant tuberculsosis (TB) is global health crisis that demands novel treatment strategies. Bacterial ATP synthase inhibitors such as bedaquiline and next-generation analogues (such as TBAJ-876) have shown promising efficacy in patient populations and preclinical studies, respectively, suggesting that selective targeting of this enzyme presents a validated therapeutic strategy for the treatment of TB. In this work, we report tetrahydronaphthalene amides (THNAs) as a new class of ATP synthase inhibitors that are effective in preventing the growth of Mycobacterium tuberculosis (M.tb) in culture. Design, synthesis and comprehensive structure-activity relationship studies for approximately 80 THNA analogues are described, with a small selection of compounds exhibiting potent (in some cases MIC90 <1 µg/mL) in vitro M.tb growth inhibition taken forward to pharmacokinetic and off-target profiling studies. Ultimately, we show that some of these THNAs possess reduced lipophilic properties, decreased hERG liability, faster mouse/human liver microsomal clearance rates and shorter plasma half-lives compared with bedaquiline, potentially addressing of the main concerns of persistence and phospholipidosis associated with bedaquiline.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study.

BACKGROUND: AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18-75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov, NCT03763877. FINDINGS: Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was -1·1% in the placebo group, -1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI -15·4 to 15·7], p=0·99), -14·3% in the 250 mg twice daily group (-13·1% [-28·1 to 1·8], p=0·084), and -14·7% in the 500 mg once daily group (-13·5% [-28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred. INTERPRETATION: PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis. FUNDING: Poxel.

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.

Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer.

PURPOSE: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study.

AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL-both peak and AUC are reduced versus baseline-and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.

Rotigotine patch prescription in inpatients with Parkinson's disease: evaluating prescription accuracy, delirium and end-of-life use.

BACKGROUND: Rotigotine patch, a trans-dermal dopamine agonist, is used acutely to replace oral dopaminergic medications for inpatients with Parkinson's disease where enteral routes are no longer available, and is also an option in end-of-life care where patients can no longer swallow. Concerns regarding acute use of Rotigotine include difficulty achieving dopaminergic equivalence, promotion of delirium/hallucinations and promotion of terminal agitation. OBJECTIVE: our objectives were to establish: (i) accuracy of Rotigotine prescribing, (ii) rates of delirium/hallucinations and (iii) rates of terminal agitation. METHOD: we retrospectively evaluated the use of Rotigotine in an inpatient population at a UK teaching hospital. Prescriptions between January 2018 and July 2019 were identified and inpatient records were analysed. OPTIMAL Calculator 2 was used as a gold standard for assessing conversion of oral dopaminergic medication to Rotigotine. RESULTS: a total of 84 inpatients were included. 25 (30%) patients were prescribed the recommended dose of Rotigotine; 31 (37%) higher and 28 (33%) lower than recommended. A total of 15 of 41 (37%) patients with dementia and 22 of 49 (45%) patients with delirium before initiation of Rotigotine inappropriately received the higher dose; 20 (24%) patients developed new/worsening delirium and 8 (10%) patients developed new/worsening hallucinations; and 59 (70%) patients were dead at time of evaluation, of these 40 (68%) died in hospital, 10 (25%) of whom experienced terminal agitation. CONCLUSIONS: acute conversion of oral dopaminergic medication to trans-dermal Rotigotine patch remains problematic despite the availability of validated tools. Inappropriate dosing may precipitate or worsen delirium/hallucinations. Use at end-of-life requires further evaluation.

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.

Dezocine prevents sufentanil-induced cough during general anesthesia induction: a meta-analysis of randomised controlled trials.

BACKGROUND: Sufentanil is one of the opioids currently used to induce general anesthesia, and cough is one of the most common complications. Many drugs have been used to prevent sufentanil-induced cough (SIC), and dezocine is one of them. Dezocine is an analgesic, acting as partial antagonist of κ-receptors and agonist of µ-receptors. The purpose of our meta-analysis is to evaluate the efficacy of dezocine on SIC. METHODS: We searched multiple databases including PubMed, Embase, ScienceDirect, the Cochrane Library, and China National Knowledge Infrastructure databases (CNKI) to identify studies that met the inclusion criteria. This meta-analysis focused on the incidence and severity of SIC after dezocine intervention, as well as adverse effects. This meta-analysis was registered on PROSPERO with reference number ID: CRD 42020144943. RESULTS: Five randomised controlled trials (RCTs) were identified, including 890 patients. Each study was a comparison of dezocine with an equal volume of 0.9% saline. When the injection dose of dezocine was 0.1 mg/kg, the incidence (pooled risk ratio (RR) = 0.03, [95% CI: 0.02 to 0.07], P < 0.00001, I2 = 0%) and severity (mild: RR = 0.07, [95% CI: 0.03 to 0.18], P < 0.00001, I2 = 0%; moderate: RR = 0.05, [95% CI: 0.02 to 0.16], P < 0.00001, I2 = 0%; severe: RR = 0.04, [95% CI: 0.01 to 0.16], P < 0.00001, I2 = 0%) of SIC were significantly decreased. There were no statistically significant differences in vital signs between the two groups based on the results of the pooled analysis. CONCLUSION: This meta-analysis showed that dezocine significantly reduced the incidence and severity of SIC in the induction of general anesthesia, but had no significant effect on vital signs. More high-quality RCTs are needed to complement existing conclusions.

Effects of dezocine and ropivacaine infiltration anesthesia on cellular immune function indicators, anesthesia recovery time and pain factors in patients with open liver resection.

The current experiment was carried out to explore the effects of dezocine combined with ropivacaine infiltration anesthesia on the anesthesia recovery time and pain factors of patients with open hepatectomy. A prospective randomized controlled method was used to select 92 patients with open liver cancer resection in our hospital from August 2017 to November 2019. The patients were divided into a study group (n=46) and a control group (n=46) using a computer-generated random number table. Both groups underwent general anesthesia, based on this, the study group was treated with ropivacaine infiltration anesthesia 10 minutes before skin incision, and dezocine was given intravenously 0.5 h before surgery, the control group was anesthetized with ropivacaine 10 minutes before the incision, and was given a saline injection 0.5 h before the operation. Compared the recovery of anesthesia (recovery time of spontaneous breathing, time to open eyes, time to extubation), the incidence of adverse reactions, and cellular immune function indicators (peripheral blood CD4+, CD4+/CD8+, NK cell levels), stress response indicators [serum blood glucose (Glu), norepinephrine (NE), adrenaline (E)], pain factors [serum dopamine (DA), neuropeptide Y (NPY), substance P (SP)] before induction of anesthesia (T0), completion of surgery (T1), 12 hours after surgery (T2), and 24 hours after surgery (T3) between the two groups, and the degree of pain (VAS score) at T2 and T3 were compared between the two groups. The levels of CD4+, CD4+/CD8+, and NK cells in peripheral blood at T1, T2, and T3 in the study group were higher than those in the control group (P<0.05); serum Glu, NE, and E levels in the study group at T1, T2, and T3 were lower than those in the control group (P<0.05); serum DA, NPY, and SP levels in the study group at T1, T2, and T3 were lower than those in the control group (P<0.05); the VAS scores of the study group at T2 and T3 were lower than those of the control group (P<0.05); the time of spontaneous breathing recovery, eyes opening and extubation in the study group were shorter than those in the control group (P<0.05); the incidence of restlessness (4.35%), transient hypertension (6.52%), and cough (2.17%) in the study group were lower than those in the control group (P<0.05). Dezocine and ropivacaine infiltration anesthesia can significantly shorten the recovery time of anesthesia and inhibit pain factor secretion in patients with open hepatectomy and can reduce the body's stress response after surgery, reduce immune function fluctuations, and can reduce the incidence of adverse reactions to anesthesia, and help promote patients' postoperative recovery.

The safety and pharmacokinetics of a novel, selective S1P1R modulator in healthy participants.

Background: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed.Results: BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.