Duration Of Action Research Articles

Delivery of nano-emulgel carrier: optimization, evaluation and in vivo anti-inflammation estimations for osteoarthritis.

Aim: Optimization and evaluation of Aceclofenac nanoemulgel for treatment for rheumatoid arthritis and reduction of GI irritation and enhancement of bioavaibility. Materials & methods: Different batches of emulgel and selected batch was proceeded for characterization like particle size, scanning electronmicroscopy, drug ingredient, in vitro release, Fourier transform infraredand x-ray diffraction in vitro inflammation and gel evaluation such as (spreadability, swelling index), ex vitro permeation, skin irritation and in vivo anti-inflammatory. Result: Emulgel showed nanometri size sustained release (79.96% in 6h), compatibility and anti-inflammatory activity compared with pure drug. Concluded that emulgels had better (nearly twice as good) anti-inflammatory action as the commercial product. Conclusion: Compared with the commercial gel, the emulgel's anti-inflammatory effect had a quicker onset and a longer duration of action.

Method of hydrothermal treatment for coal spontaneous combustion inhibition and its application

The use of coal combustion inhibitors, which are mostly sprayed on the surface of the coal that remains in the mining region (post-mining inhibition), has a significant effect on preventing spontaneous burning of coal, although their duration of action is limited. Pre-inhibition (pre-mining inhibition) prolong the inhibition duration and offers the chance to change the temperature of the inhibition fluid. This results in the suggestion of a hydrothermal inhibition strategy that emphasises the influence of inhibition fluid temperature on the inhibitory effect in order to achieve accelerated inhibition. Infrared tests and temperature-programmed oxidation are used to explore the inhibition law and mechanism of inhibition temperature on the spontaneous combustion of different coal orders. The findings demonstrated that when the inhibition temperature increased to 30 °C, 40 °C, 50 °C, 60 °C and 70 °C, the average inhibition rate and cross point temperature increased dramatically while the rates of oxygen consumption, exothermic rate, and CO production continuously dropped. Simultaneously, the coal's content of more reactive groups, such methyl and methylene, dropped, and the coal's risk to self-heat reduced. At the 70 °C inhibition temperature, the lignite coal showed the maximum inhibition rate (65.28%). This research is crucial to advancing the inhibitor's application technology and efficiency of inhibition.

Principles of the pharmacology of local anesthetics

The development of local anesthetics revolutionized the performance of painful interventions. Local anesthetics have an effect on voltage-gated sodium channels in nerve fibers and modulate the conduction of impulses. With respect to the chemical structure, local anesthetics can be divided into amide and ester types. The structural differences of local anesthetics have an influence on the duration of action, the degradation pathways and specific side effects. Severe adverse events include cardiotoxicity and neurotoxicity. In addition to basic measures, such as the monitoring and securing of vital parameters, lipid infusion represents a treatment option in cases of intoxication. The recent developments of local anesthetics are particularly concerned with the reduction of toxicity and prolonging the duration of action.

Discovery and Identification of Novel 5-Hydroxy-4H-benzo[1,4]oxazin-3-one Derivatives as Potent β2-Adrenoceptor Agonists through Structure-Based Design, Synthesis, and Biological Evaluation.

Although β2-agonists are crucial for treatment of chronic respiratory diseases, optimizing β2-agonistic activity and selectivity remains essential for achieving favorable therapeutic outcomes. A structure-based molecular design workflow was employed to discover a novel class of β2 agonists featuring a 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold, which potently stimulated β2 adrenoceptors (β2-ARs). Screening for the β2-agonistic activity and selectivity led to the identification of compound A19 (EC50 = 3.7 pM), which functioned as a partial β2-agonist in HEK-293 cells containing endogenous β2-ARs. Compound A19 exhibited significant relaxant effects, rapid onset time (Ot50 = 2.14 min), and long duration of action (>12 h) on isolated guinea pig tracheal strips, as well as advantageous pharmacokinetic characteristics in vivo, rendering A19 suitable for inhalation administration. Moreover, A19 suppressed the upregulation of inflammatory cytokines and leukocytes and improved lung function in a rat model of COPD, thereby indicating that A19 is a potential β2 agonist candidate for further study.

Comparison of bupivacaine and levobupivacaine in continuous axillary brachial plexus block

Aims: This study compares bupivacaine – lidocaine and levobupivacaine – lidocaine administrations in terms of initiation and duration of motor and sensorial blockage, total number of additional analgesic applications, analgesic amount consumed in 24 hours, side-effects and hemodynamic effects in continuous axillary brachial pleksus block in hand and forearm surgery. Methods: Thirty ASA I & II physical status patients, scheduled hand or forearm surgery were enrolled for of the two groups in a randomized study. Axillary catheter duly placed in both group with appropriate guided techniques. Patients in group B received 0. 5% bupivacaine 20 ml + 2% lidocaine 20 ml and group L received 0. 5% levobupivacaine 20 ml + 2% lidocaine 20 ml through the axillary catheter. Initiation and duration of motor and sensorial block, total number of additional analgesic applications and analgesic amount consumed in postoperative 24 hours were recorded. Pre-block, peri-operative and post-operative blood pressures and heart beat rates were also recorded. Block application duration, operation duration, tourniquet duration and demographic data of patients (age, sex, weight, and length) were recorded. Demanded and applied analgesic doses by the patient controlled analgesia devices, side effects and complications were also recorded. Results: There was no statistically significant difference between two groups in terms of initiation and duration of motor and sensorial block, amount of analgesic consumed in 24 hours, demanded and applied analgesic doses by the patient controlled analgesia devices and hemodynamic data (p>0. 05). There is a mild and positive relation between block application duration and patient weight. (p=0. 014; r=0. 444) Conclusion: Both bupivacaine+lidocaine and levobupivacaine+lidocaine combinations can safely be used in axillary continuous brachial plexus block without any difference in terms of initiation and duration of block, total analgesic amount consumed. Their duration of action and effect on hemodynamic responses are similar.

A Retrospective Comparison of Onabotulinum Toxin A and Incobotulinum Toxin A in Terms of Efficacy, Tolerability, Duration of Effect, and Pain on Injection Administration Site for the Treatment of Chronic Migraine.

Background Onabotulinum toxin A (OnA) is a well-tolerated and effective treatment for chronic migraine (CM). However, based on research indications that incobotulinum toxin A (InA) would be equally effective, a VeteransHealth Administration medical center mandated a two-year trial of InA as a more cost-effective alternative to OnA. Although InA is used for many similar indications as OnA, it is not Food and Drug Administration-approved for treating CM, and complications occurred in several patients with CM following this treatment change. We conducted this retrospective analysis to evaluate differences in the efficacy of OnA and InA and identify the reasons for the adverse effects of InA in some of these patients. Methods We performed a retrospective review of 42 patients who had been effectively treated with OnA and were then switched to InA. The differences between treatment responses to OnA and InA were assessed through the evaluation of pain on injection, number of headache days, and duration of action. Patients received injections at 10- to 13-week intervals. Those who reported severe pain on injection of InA were switched back to OnA. Results Severe burning pain on InA injection was reported by 38% of patients (nine males and seven females, i.e., a total of 16 patients out of 42 patients). One male patient reported the same degree of pain fromboth InA and OnA injections. A total of 66.7% of women with obesity and 83.3% of men with obesity or diabetes experienced severe pain on injection. Neither migraine suppression nor the duration of effect was significantly different between OnA and InA. Conclusions OnA isbetter toleratedthan InA in the treatment of CM. InA appears to effectively suppress migraines, but some patients complain of a severe localized burning sensation during the injections. Some of these patients, all of whom were previously treated with OnA, requested to switch back to OnA. This suggested that InA is not equivalent to OnA in terms of tolerability and effectiveness.The present studyfound 2.38% of patients experienced an insufficient duration of effect withInA, and none withOnA. However, these lower rates may, in part, be due to variability in injection intervals in this sample, which could be because of scheduling considerations at the Harry S. Truman Veterans Health Administration Medical Center. In cases where OnA fails because of the development of antibodies, it might be reasonable to switch to InA treatment. Reformulation of InA with a pH-buffered solution may eliminate the difference in pain on injection. InA would then be a good alternative to OnA for treating CM.

DFT and QSAR study of Catechol-O-methyltransferase (COMT) as inhibitors for Parkinson’s disease treatment

Parkinson’s disease is characterized by a lack of the neurotransmitter or cell-signaling molecule dopamine. Levodopa is a well-known drug for Parkinson’s disease since it induces dopamine. Catechol-O-methyltransferase (COMT) are enzymes that break down levodopa, limiting the amount delivered to the brain. COMT inhibitors act by extending the duration of action of levodopa, thus improving the amount of time benefit from levodopa. There are several FDA-approved COMT inhibitors used, such as Entacapone and Tolcapone. Tolcapone can penetrate blood-brain barrier (BBB), but most of the drug stays in the plasma because its high protein bound, and it has severe side effects, while Entacapone cannot penetrate BBB, which reduces drug efficiency. This study aims to design higher-efficiency drug inhibitors by investigating the physical properties in terms of total energy, total dipole moment and HOMO/LUMO band gap at DFT: B3LYP level using the LAN2DZ basis set, in addition to quantitative structure activity relationship (QSAR) calculations to test the biological activity of these drug inhibitors for the treatment of Parkinson’s disease.

Effect of high voltage discharge on germination characteristics of vetch seeds at high altitude

High-voltage electrostatic fields and low-temperature plasma technology at atmospheric pressure have an important impact on biological growth promotion. Therefore, a multi-needle-column-plate corona plasma generator is proposed in this paper. The negative corona voltammetry characteristics of multi-needle-plate electrodes and multi-needle-column-plate electrodes with different electrode spacing are investigated experimentally, and the electric field distribution of the device is simulated. The device was also applied to vetch seeds at high altitudes to investigate the effect of discharge on germination and root length. The results show that the introduction of column electrodes can effectively improve the electric field distribution of the device so that the device can provide two modes of high voltage electrostatic field and corona plasma field, and ensure the uniform treatment of seeds when the electrode spacing is 3 cm. The treatment of this device accelerates seed germination and promotes root growth, and is more effective under the combined influence of higher electric field strength, ionic wind generated by the discharge, and the active species than a single factor with a lower electric field, as well as shortening the duration of action. The high voltage electrostatic fields at −3 kV, −6 kV, and −9 kV and the corona discharge plasma fields at −12 kV, −15 kV, and −18 kV can effectively accelerate the germination of vetch seeds as well as promote the root growth under the treatment time of 10 min, 20 min, and 30 min. The optimal conditions were −9 kV for 30 min and −15 kV for 10 min, respectively.

Buffered versus Non-buffered Local Anaesthesia in Minor Oral Surgery - A Comparative Study.

Commercially available local anaesthetics are acidic solutions associated with the vasopressor sting on injection, relatively slower onset of action and pain during palatal injections. The above drawbacks can be addressed by anaesthetic buffering. This prospective study was aimed at comparing the efficacy of buffered and non-buffered local anaesthesia in the extraction of grossly decayed maxillary molar teeth in relation to pain on local infiltration, onset and duration of action of local anaesthesia. This is a prospective randomised controlled trial done on 100 patients who required bilateral extraction of maxillary molar teeth. In the study group, patients were given buffered local anaesthesia (which was prepared by mixing 2% lignocaine with 1:80,000 adrenaline and 8.4% sodium bicarbonate) before extraction. In the control group, non-buffered local anaesthesia (2% lignocaine with 1:80,000 adrenaline) was given before extraction. Statistical data confirmed that buffering reduces pain on infiltration, decreases the onset and increases the duration of action of the local anaesthesia compared to non-buffered local anaesthesia. All the parameters measured were statistically significant (P = 0.001). The study concludes that buffered local anaesthesia was more beneficial than non-buffered local anaesthesia in reducing pain on injection, providing a quicker onset of local anaesthesia and increasing the duration of action of the local anaesthesia. Buffering is a safe, easy and efficient process and should be routinely followed to provide a better experience to the patients.

Comparison of lidocaine and lidocaine-xylazine for distal paravertebral anesthesia in dairy cattle.

To determine the time of onset and duration of action of distal paravertebral blocks (DPB) in dairy cattle using lidocaine and lidocaine plus xylazine (LX). 10 healthy adult Holstein cows. Unilateral DPB were performed in 6 cows at L1, L2, and L4. They received 2 treatments (lidocaine and LX) in a blinded random crossover design. Due to treatment failure, 4 additional cows were enrolled. The lidocaine treatment received 1,800 mg (90 mL) of lidocaine, and treatment LX received 1,784 mg (89.2 mL) of lidocaine and 16 mg (0.8 mL) of xylazine. Anesthesia was assessed by response (rapid movements of the tail, directed movements of the feet, or turning of the head towards the site of the needle pricks) to 6 approximately 1-cm deep needle pricks to the paralumbar fossa with a 22-gauge hypodermic needle. The time of onset, duration of action, maximum sedation score, and average heart rate (HR) were compared between treatments. Duration of anesthesia was significantly prolonged after DPB in cows treated with LX (251.6 ± 96.94 minutes) compared to lidocaine (105.8 ± 35.9 minutes; P = .01). Treatment with LX was associated with significantly lower average heart rate (56 ± 3 beats/min) compared to cows treated with lidocaine (59 ± 3 beats/min; P = .045). The LX treatment was associated with mild sedation but was not significant (P = .063). The addition of xylazine to a lidocaine DPB provides a longer duration of anesthesia, is inexpensive and practical, and can be implemented with ease.

Supramolecular Nano‐Grid Platform to Load and Deliver Liposomes and Exosomes

In general, carriers are designed to deliver pharmaceutical (featuring small drug‐molecules) and biopharmaceutical (featuring large‐molecule drugs, e.g., antibodies, proteins, etc.) active ingredients and platform that is capable of transporting nanoparticles is rare. Herein, the fabrication of a supramolecular carrier with a nano‐grid structure for the entrapment of liposomes and exosomes is reported. The nano‐grid particles (NGP) are made of cyclodextrins as elementary units which are widely used to load drugs through host–guest inclusion complexes, whilst its secondary structure further formed the NGP tertiary architectures, enabling the entrapment of nanoparticles. The NGP features stimuli responsiveness, tunable surface charge, and good biocompatibility. The entrapped liposomes in NGP present enhanced distribution in lungs and extended duration of action in mice. And elongated release profiles for over 14 days is obtained for exosomes—making one‐of‐its‐kind unique platform to load and deliver nanoparticles.

Formulation and evaluation of floating tablet of nimesulide by direct compression method

Nimesulide has been used versatile on fever, pain, inflammation, rheumatoid arthritis, tendinitis, thrombophlebitis and trauma. Common drawbacks of conventional tablet dosage forms of nimesulide show an irritant effect on the stomach due to its weakly acidic nature along it has short duration of action leading to poor bioavailability. A Floating drug delivery system for Nimesulide leads to overcoming the problem related to an irritant on the stomach by avoiding direct contact with the mucosa. Thus, this study was designed and performed to formulate and evaluate the floating tablet of Nimesulide and determine the release pattern of the prepared formulation. Tablets were prepared by direct compression method using different polymers (HPMC, carbopol, and guar gum), either in an individual or in combination. The formulation blend was subjected to various pre-formulation and post-formulation studies including floating lag time, total floating time, hardness, friability, drug content, weight uniformity, and in-vitro dissolution. According to pre- pre-formulation study, the flow property was found to be good to passable. Similarly, all post-compression parameters of floating tablets were found to be within acceptable limits except the friability test of F1 and F2 formulations. The tablet’s floating lag time was determined to be in the range of 7-153.5 seconds, and the total floating time was in the range of 4-7 hrs. From the data of dissolution, carbopol showed a slower release of drugs than that of HPMC and guar gum. The use of carbopol as a floating polymer showed release of drugs from dosage form was 84.46% in 7 hrs and 99.10% in 3 hrs with the use of HPMC, 96.39% in 4 hrs with the use of guar gum. A combination of HPMC and guar gum released drugs in a slow release of drugs only for 3 hrs i.e. 98.02% in 3 hrs, the combination of carbopol and HPMC slowly released drugs for 6 hrs i.e. 90.43% in 6 hrs, and the combination of carbopol and guar gum showed maximum slow release of drugs for greater than 7 hrs i.e.74.16% in 7hrs. Hence, among all the formulations, F7 with the combination of carbopol and guar gum as polymer showed a maximum slowed release effect for greater than 7 hrs, which can be taken as the best batch.

Macrocycles and Acyclic Cucurbit[n]urils as Pseudo[2]catenane Partners for Long-Acting Neuromuscular Blocks and Rapid Reversal In Vivo.

Long-acting neuromuscular blocks followed by rapid reversal may provide prolonged surgeries with improved conditions by omitting repetitive or continuous administration of the neuromuscular blocking agent (NMBA), eliminating residual neuromuscular block and minimizing postoperative recovery, which, however, is not clinically available. Here, we demonstrate that imidazolium-based macrocycles (IMCs) and acyclic cucurbit[n]urils (ACBs) can form such partners by functioning as long-acting NMBAs and rapid reversal agents through a pseudo[2]catenation mechanism based on stable complexation with Ka values of over 109 M-1. In vivo experiments with rats reveal that, at the dose of 2- and 3-fold ED90, one IMC attains a duration of action corresponding to 158 or 442 min for human adults, covering most of prolonged surgeries. The block can be reversed by one ACB with recovery time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, the clinically most widely used intermediate-acting NMBA.

Optimizing Cardioplegic Solutions: A Focus on Pharmaco-Cold Strategies

This study investigates the impact of crystalloid cardioplegic solutions (CCS) on electrophysiological mechanisms and the contractile system during the diastolic phase. Extracellular solutions, categorized by ion concentration, demonstrate efficacy in inducing cardiac arrest through moderately elevated potassium or potassium-magnesium combinations, aligning with normal or slightly reduced sodium and calcium levels. Notably, the ease of equilibration with myocardial tissue enhances the protective effect, correlating with infusion volume and duration of action. However, drawbacks such as low buffering capacity and the need for reinfusion after 15-20 minutes are identified. This research sheds light on the dynamic relationship between solution composition, duration of action, and protective efficacy, providing valuable insights for refining cardioplegic protocols in cardiac surgeries. Highlights: Intracellular vs. Extracellular Impact: Explore ion concentration's influence on crystalloid cardioplegic solutions, emphasizing the choice between intracellular and extracellular formulations. Equilibration Dynamics: Investigate the direct correlation between infusion volume, duration of action, and the protective effect, emphasizing equilibration with myocardial tissue. Refining Cardioplegic Protocols: Identify limitations like low buffering capacity, necessitating reinfusion, and offer insights into strategies for enhancing cardioplegic protocols in cardiac surgeries. Keywords: Cardioplegia, Intracellular Solutions, Calcium paradox, Protective Efficacy, Cellular Metabolism

Semi-synthetic nanobody-ligand conjugates exhibit tunable signaling properties and enhanced transcriptional outputs at neurokinin receptor-1.

Antibodies have proven highly valuable for therapeutic development; however, they are typically poor candidates for applications that require activation of G protein-coupled receptors (GPCRs), the largest collection of targets for clinically approved drugs. Nanobodies (Nbs), the smallest antibody fragments retaining full antigen-binding capacity, have emerged as promising tools for pharmacologic applications, including GPCR modulation. Past work has shown that conjugation of Nbs with ligands can provide GPCR agonists that exhibit improved activity and selectivity compared to their parent ligands. The neurokinin-1 receptor (NK1R), a GPCR targeted for the treatment of pain, is activated by peptide agonists such as Substance P (SP) and neurokinin A (NKA), which induce signaling through multiple pathways (Gs , Gq and β-arrestin). In this study, we investigated whether conjugating NK1R ligands with Nbs that bind to a separate location on the receptor would provide chimeric compounds with distinctive signaling properties. We employed sortase A-mediated ligation to generate several conjugates consisting of Nbs linked to NK1R ligands. Many of these conjugates exhibited divergent and unexpected signaling properties and transcriptional outputs. For example, some Nb-NKA conjugates showed enhanced receptor binding capacity, high potency partial agonism, prolonged cAMP production, and an increase in transcriptional output associated with Gs signaling; whereas other conjugates were virtually inactive. Nanobody conjugation caused only minor alterations in ligand-induced upstream Gq signaling with unexpected enhancements in transcriptional (downstream) responses. Our findings underscore the potential of nanobody conjugation for providing compounds with advantageous properties such as biased agonism, prolonged duration of action, and enhanced transcriptional responses. These compounds hold promise not only for facilitating fundamental research on GPCR signal transduction mechanisms but also for the development of more potent and enduring therapeutics.

Soluble Angiotensin-Converting Enzyme 2 Protein Improves Survival and Lowers Viral Titers in Lethal Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection with the Delta Variant.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme 2 (ACE2) as its main receptor for cell entry. We bioengineered a soluble ACE2 protein termed ACE2 618-DDC-ABD that has increased binding to SARS-CoV-2 and prolonged duration of action. Here, we investigated the protective effect of this protein when administered intranasally to k18-hACE2 mice infected with the aggressive SARS-CoV-2 Delta variant. k18-hACE2 mice were infected with the SARS-CoV-2 Delta variant by inoculation of a lethal dose (2 × 104 PFU). ACE2 618-DDC-ABD (10 mg/kg) or PBS was administered intranasally six hours prior and 24 and 48 h post-viral inoculation. All animals in the PBS control group succumbed to the disease on day seven post-infection (0% survival), whereas, in contrast, there was only one casualty in the group that received ACE2 618-DDC-ABD (90% survival). Mice in the ACE2 618-DDC-ABD group had minimal disease as assessed using a clinical score and stable weight, and both brain and lung viral titers were markedly reduced. These findings demonstrate the efficacy of a bioengineered soluble ACE2 decoy with an extended duration of action in protecting against the aggressive Delta SARS-CoV-2 variant. Together with previous work, these findings underline the universal protective potential against current and future emerging SARS-CoV-2 variants.

Self-assembling Organogels Loaded with Tenoxicam for Local Intensive Pain and Inflammation Cure: In Vitro and In Vivo Correlation.

Due to tenoxicam (TX)'s poor aqueous solubility (0.072 mg/ml), it is poorly absorbable in the GIT, and the long-term oral administration of TX may cause severe GIT disturbances. Topical administration of TX can help in bypassing the GIT adverse effects. Therefore, in the present work, we constructed different pluronic/lecithin organogels (PLOs) for topical delivery of TX. PLO was constructed simply via direct mixing of an aqueous pluronic solution with lecithin solution. The prepared PLO formulations were characterized for their physicochemical properties including pH, drug content, visual inspection, viscosity, and spreadability. Also, the in vitro release and kinetic studies were carried out to investigate the mechanism of drug release. Moreover, the in vivo studies were carried out by investigating the anti-inflammatory and analgesic activities using albino male rats. The results showed that the modified PLOs have good physicochemical properties. The viscosity of the modified gels is a direct proportionality with both lecithin and pluronic concentrations. Also, subsequently, the drug release rate is directly proportional to gel viscosity. Moreover, the in vivo studies showed that the modified PLOs (F19) showed a significant ( < 0.05%) paw edema inhibition and pain analgesia compared with other investigated groups. Also, the results indicated that the increase in dose is accompanied by higher activity and a longer duration of action which extended to 12 h. Hence, the modified PLOs are promising safe candidates or vehicles for effective TX loading with sustained delivery behavior.

J-2156, a small molecule somatostatin type 4 receptor agonist, alleviated hindpaw hypersensitivity in the streptozotocin-induced rat model of painful diabetic neuropathy but with a 2-fold decrease in potency at an advanced stage in the model, mimicking morphine.

There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST4) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8-12-weeks (morphine-sensitive phase; Phase 1) and 16-18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30mg/kg), gabapentin (100mg/kg i.p.), subcutaneous morphine (1mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156at 30mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5h compared with 1h for gabapentin and morphine. The durations of action for all three compounds were greater than 3h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly (p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options.

Efficacy and safety of insulin glargine 300 units/mL vs insulin degludec in patients with type 1 and type 2 diabetes: a systematic review and meta-analysis.

Ultra-long-acting insulin analogs [insulin degludec (IDeg) and insulin glargine 300 units/mL (IGla-300)] offer a longer duration of action with less risk of hypoglycemia compared to other long-acting insulins. However, data about the comparative efficacy and safety are inconsistent. We searched CENTRAL, PubMed, Embase, ICTRP Search Portal, and ClinicalTrials.gov on 7 October 2022. Randomized controlled trials (RCTs) comparing the safety and efficacy of IDeg (100 or 200 units/mL) and IGla-300 in patients with type 1 or type 2 diabetes were included. Three review authors independently selected trials, assessed the risk of bias, extracted data, and evaluated the overall certainty of the evidence using GRADE. The primary outcomes were the change in glycated hemoglobin (HbA1c) and any hypoglycemia; the secondary outcomes were the change in fasting plasma glucose (FPG) and severe and nocturnal hypoglycemia. Four open-label RCTs were included (2727 participants), 3 parallel and 1 cross-over. Overall, the risk of bias assessment yielded some concern or high risk. There was a comparable change in HbA1c from baseline to the end of treatment, a mean difference of 0.07% (95% confidence interval (CI) 0.06 - 0.19; p = 0.29; 3 trials; 2652 patients; very low-certainty evidence), and a comparable rate of any hypoglycemia, rate ratio 1.02 (95% CI 0.8 - 1.3; p = 0.87; 3 trials; 2881 patients; very low-certainty evidence). IDeg resulted in more reduction in FPG compared to IGla-300, mean difference of 10.27 mg/dL (95% CI 7.25 - 13.29; p < 0.001; 3 trials; 2668 patients; low-certainty evidence). Similar rates of nocturnal and severe hypoglycemia were observed, rate ratio of 1.13 (95% CI 0.72 - 1.78; p = 0.54; 3 trials; 2668 patients; very low-certainty evidence) and 1.4 (95% CI 0.41 - 4.73; p = 0.59; 2 trials; 1952 patients; very low-certainty evidence), respectively. There is no evidence of a difference between IDeg and IGla-300 in the mean change in HbA1c and the risk of anytime, nocturnal, and severe hypoglycemia. IDeg appeared to cause a higher reduction in FPG compared to IGla-300. However, this finding should be interpreted with caution due to the small number of trials included and their high risk of bias. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022364891, identifier CRD42022364891.

Effect of ultrasound-guided continuous erector spinae plane block on postoperative pain and inflammatory response in patients undergoing modified radical mastectomy for breast cancer: study protocol for a randomised controlled trial

BackgroundA single injection of local anaesthetic (LA) in the erector spinae plane block (ESPB) can reduce pain after modified radical mastectomy (MRM) surgery, but the duration of analgesia is affected by the duration of the LA. The aim of this study is to investigate the effect of continuous ESPB on acute and chronic pain and inflammatory response after MRM surgery.MethodsIn this prospective, randomised, controlled trial, we will recruit 160 patients, aged 18–80 years, scheduled for elective MRM surgery under general anaesthesia. They will be randomly assigned to two groups: a continuous ESPB group (group E) and a sham block group (group C). Both groups of patients will have a nerve block (group C pretended to puncture) and an indwelling catheter fixed prior to surgery. Electronic pumps containing LA are shielded. The primary outcome is the total consumption of analgesic agents. The secondary outcomes include the levels of inflammation-related cytokines; the occurrence of chronic pain (post-mastectomy pain syndrome, PMPS); static and dynamic pain scores at 2, 6, 12, 24 and 48 h postoperatively; and post-operative and post-puncture adverse reactions.DiscussionAnalgesia after MRM surgery is important and chronic pain can develop when acute pain is prolonged, but the analgesic effect of a nerve block with a single injection of LA is limited by the duration of drug action. The aim of this trial is to investigate whether continuous ESPB can reduce acute pain after MRM surgery and reduce the incidence of chronic pain (PMPS), with fewer postoperative analgesic drug-related complications and less inflammatory response. Continuous ESPB and up to 12 months of follow-up are two innovations of this trial.Trial registrationChinese Clinical Trial Registry (https://www.chictr.org.cn/) ChiCTR2200061935. Registered on 11 July 2022. This trial is a prospective registry with the following registry names: Effect of ultrasound-guided continuous erector spinae plane block on postoperative pain and inflammatory response in patients undergoing modified radical mastectomy for breast cancer.