Efficacy and safety of sedation with dexmedetomidine in adults undergoing gastrointestinal endoscopic procedures: systematic review and meta-analysis of randomized controlled trials.

Background: The sedative role of dexmedetomidine (DEX) in gastrointestinal endoscopic procedures is unclear. We performed this systematic review and meta-analysis to assess the efficacy and safety of sedation with DEX during gastrointestinal endoscopic procedures with a view to providing evidence-based references for clinical decision-making. Methods: The PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) that compared DEX with different sedatives comparators (such as propofol, midazolam, and ketamine) for sedation in a variety of adult gastrointestinal endoscopic procedures from inception to 1 July 2022. Standardized mean difference (SMD) and weighted mean difference (WMD) with 95% confidence interval (CI) or pooled risk ratios (RR) with 95% CI were used for continuous outcomes or dichotomous outcomes, respectively, and a random-effect model was selected regardless of the significance of the heterogeneity. Results: Forty studies with 2,955 patients were assessed, of which 1,333 patients were in the DEX group and 1,622 patients were in the control (without DEX) group. The results suggested that the primary outcomes of sedation level of DEX are comparable to other sedatives, with similar RSS score and patient satisfaction level, and better in some clinical outcomes, with a reduced risk of body movements or gagging (RR: 0.60; 95% CI: 0.37 to 0.97; p = 0.04; I2 = 68%), and a reduced additional requirement for other sedatives, and increased endoscopist satisfaction level (SMD: 0.41; 95% CI: 0.05 to 0.77; p = 0.03; I2 = 86%). In terms of secondary outcomes of adverse events, DEX may benefit patients in some clinical outcomes, with a reduced risk of hypoxia (RR:0.34; 95% CI: 0.20 to 0.55; p < 0.0001; I2 = 52%) and cough (RR: 0.25; 95% CI: 0.12 to 0.54; p = 0.0004; I2 = 0%), no significant difference in the risk of hypotension, while an increased risk of bradycardia (RR: 3.08; 95% CI: 2.12 to 4.48; p < 0.00001; I2 = 6%). Conclusion: This meta-analysis indicates that DEX is a safe and effective sedative agent for gastrointestinal endoscopy because of its benefits for patients in some clinical outcomes. Remarkably, DEX is comparable to midazolam and propofol in terms of sedation level. In conclusion, DEX provides an additional option in sedation for gastrointestinal endoscopic procedures. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#searchadvanced.

M6P-modified solid lipid nanoparticles loaded with matrine for the treatment of fibrotic liver.

Liver fibrosis is a key pathological process shared by the progression of various chronic liver diseases. Treatment of liver fibrosis can effectively block the occurrence and development of hepatic cirrhosis or even carcinoma. Currently, there is no effective drug delivery vehicle for curing liver fibrosis. In this study, we designed matrine (MT)-loaded mannose 6-phosphate (M6P) modified human serum albumin (HSA) conjugated solid lipid nanoparticles (SLN), named M6P-HSA-MT-SLN for treatment of hepatic fibrosis. We demonstrated that M6P-HSA-MT-SLN exhibited controlled and sustained release properties and good stability over 7 days. The drug release experiments showed that M6P-HSA-MT-SLN exhibited slow and controlled drug release characteristics. In addition, M6P-HSA-MT-SLN showed a significant targeted ability to fibrotic liver. Importantly, in vivo studies indicated that M6P-HSA-MT-SLN could significantly improve histopathological morphology and inhibit the fibrotic phenotype. In addition, in vivo experiments demonstrate that M6P-HSA-MT-SLN could reduce the expression of fibrosis markers and alleviate the damage of liver structure. Hence, the M6P-HSA-MT-SLN provide a promising strategy to deliver therapeutic agents to fibrotic liver to prevent liver fibrosis.

The Cuproptosis-Related Long Noncoding RNA Signature Predicts Prognosis and Immune Cell Infiltration in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC), ranking as one of the most common malignant tumors, is one of the leading causes of cancer death, with a poor prognosis. Cuproptosis, a novel programmed cell death modality that has just been confirmed recently, may play an important role in HCC prognosis. Long noncoding RNA (LncRNA) is a key participant in tumorigenesis and immune responses. It may be of great significance to predict HCC based on cuproptosis genes and their related LncRNA. Methods: The sample data on HCC patients were obtained from The Cancer Genome Atlas (TCGA) database. Combined with cuproptosis-related genes collected from the literature search, expression analysis was carried out to find cuproptosis genes and their related LncRNAs significantly expressed in HCC. The prognostic model was constructed by least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression. The feasibility of these signature LncRNAs used for the evaluation of the overall survival rate in HCC patients as independent factors was investigated. The expression profile of cuproptosis, immune cell infiltration, and the status of somatic mutation were analyzed and compared. Results: A prognostic model of HCC consisting of seven cuproptosis gene-related LncRNA signatures was constructed. Multiple verification methods have showed that this model can accurately predict the prognosis of HCC patients. It was showed that the classified high-risk group under the risk score of this model had worse survival status, more significant expression of the immune function, and higher mutation frequency. During the analysis, the cuproptosis gene CDKN2A was found to be most closely related to LncRNA DDX11-AS1 in the expression profile of HCC patients. Conclusion: The cuproptosis-related signature LncRNA in HCC was identified, on the basis of which a model was constructed, and it was verified that it can be used to predict the prognosis of HCC patients. The potential role of these cuproptosis-related signature LncRNAs as new targets for disease therapy in antagonizing HCC development was discussed.

Microneedle-mediated delivery of Ziconotide-loaded liposomes fused with exosomes for analgesia.

Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine and systemic analgesics. As it can only work in the brain and cerebrospinal fluid, intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury, diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain. BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95 nm and a Zeta potential of -7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to -3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC.

A mechanically tough and ultra-swellable microneedle for acute gout arthritis.

Acute gout arthritis (AGA) remains the fundamental research focus in the entire medical field. Hydrogel microneedles (HMNs) loaded with therapeutic molecules such as colchicine (Col) have been developed as a new tool for the management of AGA in a minimally invasive manner. However, the incompatible mechanical and swelling properties of HMNs limited the diffusion of the drug from the HMN system, which remains a challenge for practical use. Here, a mechanically tough (11.53 N per needle) and super-swelling (2708%) hydrogel microneedle (HMNs) composed of a uniform network structure was developed using a UV-responsive crosslinker through in situ photopolymerization for percutaneous delivery of Col. Such HMNs and Col loaded HMNs (Col-HMNs) present excellent biocompatibility. Moreover, Col-HMNs present considerable anti-inflammatory effects in vivo through down-regulated inflammatory responses such as related cytokines IL-1ß, IL-6, and TNF-α. These results demonstrated that the mechanically tough and super-swelling HMNs could be a promising tool for effective Col delivery to relieve AGA.

Preparation of pectin-chitosan hydrogels based on bioadhesive-design micelle to prompt bacterial infection wound healing.

The aim of this study was to design a pectin-chitosan (PEC-CS) hydrogel loaded with a bioadhesive-design micelle containing large amount of ciprofloxacin for antibacterial and healing wound applications. Pectin and chitosan are crosslinked in a safe and convenient way, and the PEC-CS hydrogel have high water content (>95 %), strong water absorption (15,000 %), good water retention (>10,000 % at 30 % RH for 12 h), and the PEC-CS hydrogels showed no cytotoxicity and hemolysis, thus providing a humid microenvironment suitable for wound. Additionally, the dopamine modified carrier can greatly improve the solubility and retention time in the wound of ciprofloxacin, effectively increase the efficiency of drug loading into the PEC-CS hydrogels and exert antibacterial activity in the wound for a long time. In vitro and in vivo pharmacodynamics experiments have shown that PEC-CS#CIP@DPDMCs hydrogels can resist bacteria and promote wound healing. Thus，The PEC-CS#CIP@DPDMCs hydrogels can be a potential anti-infective hydrogel excipient.

Reactive Oxygen Species-Responsive Polypeptide Drug Delivery System Targeted Activated Hepatic Stellate Cells to Ameliorate Liver Fibrosis.

Hepatic fibrosis is a chronic liver disease that lacks effective pharmacotherapeutic treatments. As part of the disease's mechanism, hepatic stellate cells (HSCs) are activated by damage-related stimuli to secrete excessive extracellular matrix, leading to collagen deposition. Currently, the drug delivery system that targets HSCs in the treatment of liver fibrosis remains an urgent challenge due to the poor controllability of drug release. Since the level of reactive oxygen species (ROS) increases sharply in activated HSCs (aHSCs), we designed ROS-responsive micelles for the HSC-specific delivery of a traditional Chinese medicine, resveratrol (RES), for treatment of liver fibrosis. The micelles were prepared by the ROS-responsive amphiphilic block copolymer poly(l-methionine-block-Nε-trifluoro-acetyl-l-lysine) (PMK) and a PEG shell modified with a CRGD peptide insertion. The CRGD-targeted and ROS-responsive micelles (CRGD-PMK-MCs) could target aHSCs and control the release of RES under conditions of high intracellular ROS in aHSCs. The CRGD-PMK-MCs treatment specifically enhanced the targeted delivery of RES to aHSCs both in vitro and in vivo. In vitro experiments show that CRGD-PMK-MCs could significantly promote ROS consumption, reduce collagen accumulation, and avert activation of aHSCs. In vivo results demonstrate that CRGD-PMK-MCs could alleviate inflammatory infiltration, prevent fibrosis, and protect hepatocytes from damage in fibrotic mice. In conclusion, CRGD-PMK-MCs show great potential for targeted and ROS-responsive controlled drug release in the aHSCs of liver fibrosis.

Macrophages, Chronic Inflammation, and Insulin Resistance.

The prevalence of obesity has reached alarming levels, which is considered a major risk factor for several metabolic diseases, including type 2 diabetes (T2D), non-alcoholic fatty liver, atherosclerosis, and ischemic cardiovascular disease. Obesity-induced chronic, low-grade inflammation may lead to insulin resistance, and it is well-recognized that macrophages play a major role in such inflammation. In the current review, the molecular mechanisms underlying macrophages, low-grade tissue inflammation, insulin resistance, and T2D are described. Also, the role of macrophages in obesity-induced insulin resistance is presented, and therapeutic drugs and recent advances targeting macrophages for the treatment of T2D are introduced.

Prebiotic-like cyclodextrin assisted silybin on NAFLD through restoring liver and gut homeostasis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with no currently approved treatment. The natural compound silybin (SLN) has versatile hepatoprotective efficacy with negligible adverse effects; however, poor absorption limits its clinical applications. Gut microbiota has been proposed to play a crucial role in the pathophysiology of NAFLD and targeted for disease control. Cyclodextrins, the cyclic oligosaccharides, were documented to have various health benefits with potential prebiotic properties. This study aimed to develop a silybin-2-hydroxypropyl-ß-cyclodextrin inclusion (SHßCD) to improve the therapeutic efficacy of SLN and elucidate the mechanisms of improvement. The results showed that SLN formed a 1:1 stoichiometric inclusion complex with HP-ß-CD. The solubility of SLN was increased by generating SHßCD, resulting in improved drug permeability and bioavailability. In high-fat diet (HFD)-fed hamsters, SHßCD modulated gut health by restoring the gut microbiota and intestinal integrity. SHßCD showed superior anti-lipid accumulation, antioxidant, and anti-inflammatory effects compared with SLN alone. Transcriptome analysis in the liver tissue implied that the improved inflammation and/or energy homeostasis was the potential mechanism. Therefore, SHßCD may be a promising alternative for the treatment of NAFLD, attributing to the dual functions of HßCD on drug absorption and gut microbial homeostasis.

Bicyclol Alleviates Atherosclerosis by Manipulating Gut Microbiota.

Atherosclerosis (AS) is associated with high morbidity and mortality, thus imposing a growing burden on modern society. Herb-derived bicyclol (BIC) is a versatile bioactive compound that can be used to treat AS. However, its efficacy in AS is not yet described. Here, it is shown that BIC normalizes gut microflora dysbiosis induced by a high fat diet in Apoe(-/-) mice. Metagenome-wide association study analysis verifies that the modulation on carbohydrate-active enzymes and short-chain fatty acid generating genes in gut flora is among the mechanisms. The gut healthiness, especially the gut immunity and integrity, is restored by BIC intervention, leading to improved systemic immune cell dynamic and liver functions. Accordingly, the endothelial activation, macrophage infiltration, and cholesterol ester accumulation in the aortic arch are alleviated by BIC to lessen the plaque onset. Moreover, it is proved that the therapeutic effect of BIC on AS is transmissible by fecal microbiota transplantation. The current study, for the first time, demonstrates the antiatherosclerotic effects of BIC and shows that its therapeutic value can at least partially be attributed to its manipulation of gut microbiota.

Design of Hepatic Targeted Drug Delivery Systems for Natural Products: Insights into Nomenclature Revision of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-dysfunction-associated fatty liver disease (MAFLD), affects a quarter of the worldwide population. Natural products have been extensively utilized in treating NAFLD because of their distinctive advantages over chemotherapeutic drugs, despite the fact that there are no approved drugs for therapy. Notably, the limitations of many natural products, such as poor water solubility, low bioavailability in vivo, low hepatic distribution, and lack of targeted effects, have severely restricted their clinical application. These issues could be resolved via hepatic targeted drug delivery systems (HTDDS) that boost clinical efficacy in treating NAFLD and decrease the adverse effects on other organs. Herein an overview of natural products comprising formulas, single medicinal plants, and their crude extracts has been presented to treat NAFLD. Also, the clinical efficacy and molecular mechanism of active monomer compounds against NAFLD are systematically discussed. The targeted delivery of natural products via HTDDS has been explored to provide a different nanotechnology-based NAFLD treatment strategy and to make suggestions for natural-product-based targeted nanocarrier design. Finally, the challenges and opportunities put forth by the nomenclature update of NAFLD are outlined along with insights into how to improve the NAFLD therapy and how to design more rigorous nanocarriers for the HTDDS. In brief, we summarize the up-to-date developments of the NAFLD-HTDDS based on natural products and provide viewpoints for the establishment of more stringent anti-NAFLD natural-product-targeted nanoformulations.

A novel α-(8-quinolinyloxy) monosubstituted zinc phthalocyanine nanosuspension for potential enhanced photodynamic therapy.

OBJECTIVE: To prepare α-(8-quinolinyloxy) monosubstituted phthalocyanine zinc nanosuspension (ZnPc-NS) for photodynamic therapy by intravenous administration. METHODS: The formulation and preparation technology of ZnPc-NS were assessed by particle size using the precipitation-high pressure homogenization method. The efficacy of ZnPc-NS was evaluated based on particle size, zeta potential, sedimentation ratio, TEM imaging, stability assessment, photodynamic activity and safety. RESULTS AND DISCUSSION: The content, average particle size, polydispersity and photodegradation constant of ZnPc-NS were 0.2 mg/ml, 219.7 ± 7.41 nm, 0.19 ± 0.02 and 0.006, respectively. The photosensitization rate of singlet oxygen (1O2) of the ZnPc-NS was three times higher than that of the ZnPc DMF solution. ZnPc-NS exhibited optimal antitumor activity in HepG2 cells under light exposure and low photo- and non-light-associated toxicity in HELFX cells. In addition, low hemolysis and vascular stimulation were evident in the experiments performed. CONCLUSION: The ZnPc-NS exhibited optimal stability, faster photosensitization rate of 1O2, and optimal antitumor activity and safety than the ZnPc DMF solution, which could provide potential support for further research and development.

Borneol-mediated vardenafil hydrochloride patch for pediatric pulmonary arterial hypertension: Preparation, characterization and in vivo study.

BACKGROUND: Pediatric pulmonary arterial hypertension (PPAH) is a malignant progressive rare disease characterized by restricted pulmonary artery blood flow and progressively increasing blood pressure, which has shorter survival time of only about 10 months as compared to adults. Previous studies have shown that low-dose vardenafil hydrochloride (Var) could significantly improve the symptoms of PPAH. However, Var is currently available only in tablet form in the market for erectile dysfunction, and no special preparation is available for PPAH. METHODS: In this study, borneol-mediated vardenafil hydrochloride patch (BO-VarP) with sodium polyacrylate as the skeleton material was prepared by coating method, which was characterized by temperature resistance, formability, adhesive force, skin irritation and in vitro permeation. Blood concentration of optimized BO-VarP was measured by LC-MS/MS using intragastric administration (i.g.) as a control, and pharmacodynamic studies were conducted using a rat model of pulmonary arterial hypertension induced by monocrotaline. RESULTS AND DISCUSSION: Optimized BO-VarP showed good appearance, with optimal temperature resistance and formability, appropriate adhesive force and low skin irritation, and its cumulative permeation flux was 14.9 times higher than patch without penetration enhancer. The blood concentration within therapeutic window of BO-VarP lasted longer than i.g., and BO-VarP could improve symptoms of PPAH by reducing pulmonary arterial pressure and right heart hypertrophy index. CONCLUSION: BO-VarP had good therapeutic effect in PPAH rats and suitable compliance in children, which provided a potential industrial transdermal delivery system for the treatment of PPAH.

Liver-target nanotechnology facilitates berberine to ameliorate cardio-metabolic diseases.

Cardiovascular and metabolic disease (CMD) remains a main cause of premature death worldwide. Berberine (BBR), a lipid-lowering botanic compound with diversified potency against metabolic disorders, is a promising candidate for ameliorating CMD. The liver is the target of BBR so that liver-site accumulation could be important for fulfilling its therapeutic effect. In this study a rational designed micelle (CTA-Mic) consisting of α-tocopheryl hydrophobic core and on-site detachable polyethylene glycol-thiol shell is developed for effective liver deposition of BBR. The bio-distribution analysis proves that the accumulation of BBR in liver is increased by 248.8% assisted by micelles. Up-regulation of a range of energy-related genes is detectable in the HepG2 cells and in vivo. In the high fat diet-fed mice, BBR-CTA-Mic intervention remarkably improves metabolic profiles and reduces the formation of aortic arch plaque. Our results provide proof-of-concept for a liver-targeting strategy to ameliorate CMD using natural medicines facilitated by Nano-technology.

Enhanced transdermal permeability and drug deposition of rheumatoid arthritis via sinomenine hydrochloride-loaded antioxidant surface transethosome.

Background: Transdermal drug delivery system (TDDS) curing rheumatoid arthritis (RA) for long-term treatment can improve patients' compliance and reduce the accumulation of drug side effects. However, TDDS is constrained by the tight junction of the stratum corneum and low permeation efficiency. It is necessary to adopt proper permeation methods to ensure the therapeutic effect. The transethosome (TE), which is derived from transfersome and ethosome (E), containing a high content of ethanol along with an edge activator or permeation enhancer, has superior deformability and higher permeation efficiency. Methods and Results: In this study, sinomenine hydrochloride-loaded TE was decorated with ascorbic acid to form antioxidant surface transethosome (AS-TE). It was revealed that TE and AS-TE containing sodium deoxycholate can effectively increase the entrapment efficiency of hydrophilic drug, and has superior deformability and higher permeation efficiency than E group. The plasma pharmacokinetics of rabbits showed that TE group and AS-TE group had similar blood concentration and bioavailability; however, micro-dialysis on synovial fluid demonstrated that AS-TE group had higher drug concentration. In RA rat models, the alleviation of the joint swell of AS-TE group was more obvious in the course of 3 weeks of treatment. The inflammatory cytokines and erythrocyte sedimentation rate were significantly lower than those in the negative control group and TE1 group. Conclusion: AS-TE, which can enhance transdermal permeability and drug deposition for the oxidant stress of RA, had further research potential to serve as a TDDS of RA.

Synthesis of High Purified Tulobuterol and Its Study of the Organic Impurities.

The synthetic condition of tulobuterol was optimized to gain lower impurity content. Two intermediates were analyzed, and three degradation impurities were isolated using preparative liquid chromatography for the first time and subsequently characterized by various techniques. Possible degradation impurities were deduced by an oxidative mechanism. Two intermediate impurities were detected: α-bromo-2-chloroacetophenone and 1-(2-chlorophenyl)-2-bromoethanol. Three unreported degradation impurities were found and characterized as N-tert-butyl glycine, o-chloro-benzoic acid and chlorobenzene. The single crystal structure of tulobuterol was firstly reported.

Design, characterization and comparison of transdermal delivery of colchicine via borneol-chemically-modified and borneol-physically-modified ethosome.

Gout is a kind of joint disease characterized by the accumulation of monosodium urate (MSU) crystals in the joint and its surrounding tissue, causing persistent hyperuricemia. Colchicine is the first choice of treatment for acute gout attacks. Due to strong toxicity of colchicines oral tablets, there are high fluctuations of blood drug concentration and serious irritation of gastrointestinal tract, and hence a transdermal preparation can help to slow down the blood drug concentration, reduce the frequency of drug taking, and improve the patients' compliance of the drug. The ethosome is a lipid carrier with high concentration of ethanol and has been proved to promote the penetration of drugs into the skin. Borneol (BO) is an excellent penetration enhancer in Chinese medicine, which can promote the entry of drugs into the skin. This paper prepared the borneol-physically-modified colchicine ethosome (COL-bpES) and used the prepared borneol-dioleoyl phosphoethanloamine (BO-DOPE) to prepare borneol-chemically-modified colchicine ethosome (COL-bcES). Compared to the free colchicine aqueous solution (free COL) and normal colchicine ethosome (COL-ES), the borneol-modified colchicine ethosome (COL-bES) demonstrated better drug penetration effect, while the particle size of the COL-bcES was lower than that of the COL-bpES. Toxicity, in vitro diffusion, pharmacokinetics and pharmacodynamics are superior to those of COL-bpES, providing a better delivery system for the treatment of small molecule inflammatory drugs.

A Novel Dantrolene Sodium-Loaded Mixed Micelle Containing a Small Amount of Cremophor EL: Characterization, Stability, Safety and Pharmacokinetics.

Dantrolene sodium (DS) is the only drug specifically used for the treatment of malignant hyperthermia. Nevertheless, its clinical application is significantly restricted due to its aqueous insolubility and the limited formulations available in clinical practice. In order to solve these problems, a novel mixed micelle composed of phospholipid and Cremophor EL was designed and evaluated. The mixed micelle was prepared using a stirring- ultrasonic method. The Dynamic Light Scattering (DLS) results showed that the micelle was small in size (12.14 nm) and narrowly distributed (PdI = 0.073). Transmission Electron Microscopy (TEM) images showed that the micelle was homogeneous and spherical. The stability study indicated that the system was stable for storage and dilution with distilled water, while the safety testing showed that the micelle was safe for intravenous administration with low hemolysis rates and low allergic reaction rates. In the pharmaceutics study, the Cmax and AUC0-t of the DS-loaded micelle were 4- and 4.5- folds higher than that of the DS. Therefore, the constructed phospholipid-Cremophor EL mixed micelle is a promising drug delivery system for DS.