Association of S(+) ketamine, dexmedetomidine and butorphanol for chemical restraint in scarlet macaws (Ara macao) / Associação cetamina S(+), dexmedetomidina e butorfanol na contenção química de araracangas (Ara macao)

The present study aimed at assessing the effects of combining 20 mg/kg S(+) ketamine with 25 µg/kg dexmedetomidine and 0.4 mg/kg butorphanol on the physiological parameters and anesthetic recovery time and score of eight captive scarlet macaw (Ara macao) specimens. These specimens were captured at the Marabá Zoobotanic Foundation (Fundação Zoobotânica de Marabá), Pará, using butterfly and mist nets, and subsequently subjected to the proposed protocol. The following physiological parameters were evaluated: heart rate (HR), respiratory rate (RR), saturation of peripheral oxygen (SpO2), body temperature (BT), and non-invasive blood pressure 5 min after drug administration (M0) and every 10 min thereafter (M1‒M5), with a total of 55 min of analysis of anesthetic effects. Glycemia was measured 5 min after drug administration and every 30 min thereafter. Anesthetic induction and recovery times were also determined. Among the parameters evaluated in this study, both HR and BT significantly decreased throughout the anesthetic period, with the lowest levels at 55 min after drug administration (M5). In contrast, RR did not significantly differ, and all animals remained stable, maintaining an RR close to a mean of 20 ± 8 cpm. Throughout the anesthetic period, SpO2was 92 ± 5%, with no significant difference. The birds remained under spontaneous ventilation and without oxygen supplementation. Systolic, diastolic, and mean blood pressures remained stable, with no significant differences in any of these measurements. At M0 and M3, the glycemia decreased slightly, albeit with no significant difference justifying an adverse effect or even hypoglycemia. The anesthetic induction time, from M0 to decubitus, was 2.4 ± 0.7 min. The anesthetic recovery time, from M0 to effortless bipedal position and adequate phalangeal flexion, was 99.3 ± 32.4 min. The sedation was assessed as intense, and the anesthetic recovery was rated excellent in 62.5% and good in 37.5% of the animals.(AU)

O presente estudo objetivou avaliar os efeitos do uso da cetamina S(+) 20 mg/kg associada à dexmedetomidina 25 µg/kg e butorfanol 0,4 mg/kg sobre os parâmetros fisiológicos, tempo e qualidade da recuperação anestésica de araracangas (Ara macao). Foram utilizados oito espécimes de Ara macao cativas da Fundação Zoobotânica de Marabá, Pará. A captura foi realizada com o uso de puçá e rede de contenção e em seguida as aves foram submetidas ao protocolo proposto. Foram avaliados: frequência cardíaca, frequência respiratória, saturação parcial da oxihemoglobina (SpO2), temperatura corporal e pressão arterial não-invasiva a partir de 5 minutos após a aplicação dos fármacos (M0) e a cada 10 minutos seguintes (M1, M2, M3, M4 e M5), totalizando 55 minutos de contemplação dos efeitos anestésicos. A glicemia foi avaliada aos 5 minutos da aplicação dos fármacos e repetida após 30 minutos. Também foi determinado o tempo de indução e de recuperação. Dentre os parâmetros avaliados, a frequência cardíaca e a temperatura demonstraram queda estatisticamente significativa ao longo do período anestésico, ambas com os menores valores registrados aos 55 minutos após a aplicação dos fármacos (M5). A frequência respiratória não apresentou diferença estatística e todos os animais se mantiveram estáveis e com a frequência próxima a média de 20±8mpm. A saturação da oxihemoblobina (SpO2) ao longo do período anestésico foi de 92±5%, não houve diferença estatisticamente relevante, as aves permaneceram sob ventilação espontânea e sem suplementação de oxigênio. As pressões arteriais sistólica, diastólica e média, mantiveram-se estáveis e não houve diferença estatística para nenhuma dessas medidas. A glicemia, mensurada em M0 e M3 demonstrou queda discreta, sem diferença significativa capaz de justificar um efeito adverso ou mesmo hipoglicemia. O tempo de indução, desde aplicação dos anestésicos até o decúbito, foi de 2,4±0,7 minutos. O tempo de recuperação, compreendido desde a aplicação dos fármacos (M0) até a constatação da posição bipedal sem esforço e adequada flexão das falanges, foi de 99,3±32,4 minutos. A qualidade de sedação foi considerada intensa e a recuperação anestésica foi classificada como ótima para 62,5% e boa para 37,5% dos animais.(AU)

Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor.

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α2A-adrenergic receptor (α2AAR), seeking new α2AAR agonists chemotypes that lack the sedation conferred by known α2AAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential Gi and Go signaling. Experimental structures of α2AAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC50) of 52 nanomolar] and two analogs, '7075 and PS75 (EC50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

Activation of PI3K/Akt/HIF-1α Signaling is Involved in Lung Protection of Dexmedetomidine in Patients Undergoing Video-Assisted Thoracoscopic Surgery: A Pilot Study.

BACKGROUND: Lung resection and one lung ventilation (OLV) during video-assisted thoracoscopic surgery (VATS) may lead to acute lung injury. Dexmedetomidine (DEX), a highly selective α2 adrenergic receptor agonist, improves arterial oxygenation in adult patients undergoing thoracic surgery. The aim of this pilot study was to explore possible mechanism related to lung protection of DEX in patients undergoing VATS. PATIENTS AND METHODS: Seventy-four patients scheduled for VATS were enrolled in this study. Three timepoints (before anesthesia induction (T0), 40 min after OLV (T1), and 10 min after two-lung ventilation (T2)) of arterial blood gas were obtained. Meanwhile, lung histopathologic examination, immunohistochemistry analysis (occludin and ZO-1), levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in lung tissue and plasma, and activation of phosphoinositide-3-kinase (PI3K)/AKT/hypoxia-inducible factor (HIF)-1α signaling were detected. Postoperative outcomes including duration of withdrawing the pleural drainage tube, length of hospital stay, hospitalization expenses, and postoperative pulmonary complications (PPCs) were also recorded. RESULTS: Sixty-seven patients were randomly divided into DEX group (group D, n=33) and control group (group N, n=34). DEX improved oxygenation at T1 and T2 (group D vs group N; T1: 191.8 ± 49.8 mmHg vs 159.6 ± 48.1 mmHg, P = 0.009; T2: 406.0 mmHg [392.2-423.7] vs 374.5 mmHg [340.2-378.2], P = 0.001). DEX alleviated the alveolar capillary epithelial structure damage, increased protein expression of ZO-1 and occludin, inhibited elevation of the expression of TNF-α and IL-6 in lung tissue and plasma, and increased protein expression of p-PI3K, p-AKT and HIF-1α. Dex administered had better postoperative outcomes with less risk of PPCs and hospitalization expenses as well as shorter duration of withdrawing the pleural drainage tube and length of hospital stay. CONCLUSION: Activation of PI3K/Akt/HIF-1α signaling might be involved in lung protection of DEX in patients undergoing VATS.

Dexmedetomidine promotes the progression of hepatocellular carcinoma through hepatic stellate cell activation.

Dexmedetomidine (DEX) is an anesthetic that is widely used in the clinic, and it has been reported to exhibit paradoxical effects in the progression of multiple solid tumors. In this study, we sought to explore the mechanism by which DEX regulates hepatocellular carcinoma (HCC) progression underlying liver fibrosis. We determined the effects of DEX on tumor progression in an orthotopic HCC mouse model of fibrotic liver. A coculture system and a subcutaneous xenograft model involving coimplantation of mouse hepatoma cells (H22) and primary activated hepatic stellate cells (aHSCs) were used to study the effects of DEX on HCC progression. We found that in the preclinical mouse model of liver fibrosis, DEX treatment significantly shortened median survival time and promoted tumor growth, intrahepatic metastasis and pulmonary metastasis. The DEX receptor (ADRA2A) was mainly expressed in aHSCs but was barely detected in HCC cells. DEX dramatically reinforced HCC malignant behaviors in the presence of aHSCs in both the coculture system and the coimplantation mouse model, but DEX alone exerted no significant effects on the malignancy of HCC. Mechanistically, DEX induced IL-6 secretion from aHSCs and promoted HCC progression via STAT3 activation. Our findings provide evidence that the clinical application of DEX may cause undesirable side effects in HCC patients with liver fibrosis.

Activation of the α2B adrenoceptor by the sedative sympatholytic dexmedetomidine.

The α2 adrenergic receptors (α2ARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. α2ARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective α2AR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective αAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to ßAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the α2BAR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of α2AR-selective activation and provides insights into Gi/o coupling specificity.

Physicochemical Compatibility of Dexmedetomidine With Parenteral Nutrition.

BACKGROUND: Dexmedetomidine is an α2-agonist used as a sedative agent in the intensive care setting. Simultaneous administration of dexmedetomidine and parenteral nutrition (PN) may be required. The aim of this study was to evaluate the physicochemical compatibility of dexmedetomidine Y-site administered with PN. METHODS: Three PN and 3 dexmedetomidine solutions were compounded. The tested infusion rate for PN was 66 mL/h. For dexmedetomidine, we considered the initial and maximum infusion rates (0.7 and 1.4 µg/kg/h) detailed in the data sheet. Taking this into account and considering a weight range of 55-95 kg, we tested 2 dexmedetomidine infusion rates (10 and 36 mL/h). The samples obtained were examined visually against light. pH was analyzed with a pH meter. Mean fat droplet diameter was determined by dynamic light scattering. Quantification of dexmedetomidine concentration was carried out by ultraperformance liquid chromatography-high-resolution mass spectrometry. For each PN-dexmedetomidine admixture, tests were performed in triplicate. RESULTS: No alterations were observed by visual inspection. Average pH was 6.25 ± 0.01. Droplet diameter remained below 500 nm (298 ± 10 nm for 10-mL/h rate and 303 ± 5 nm for 36-mL/h rate). Dexmedetomidine concentrations at t = 0 were 519 ± 31 ng/mL and 1391 ± 90 ng/mL for 10- and 36-mL/h infusion rates, respectively. At t = 24 hours, the concentrations obtained were 494 ± 22 and 1332 ± 102 ng/mL, which translates into ≥90% of the initial concentrations. CONCLUSION: Dexmedetomidine is physicochemically compatible with PN during simulated Y-site administration at the tested infusion rates.

Probing the Role of Ion-Pair Strategy in Controlling Dexmedetomidine Penetrate Through Drug-in-Adhesive Patch: Mechanistic Insights Based on Release and Percutaneous Absorption Process.

The purpose of present study was to develop a controlled release drug-in-adhesive patch for transdermal delivery of dexmedetomidine (Dex) using ion-pair technique. Based on the in vitro transdermal experiment, the role of ion-pair on the Dex release behavior and percutaneous absorption process was also investigated. Fourier transform infrared spectroscopy (FTIR), molecular modeling, differential scanning calorimetry (DSC), and rheological test were conducted to probe the effect of ion-pair on the Dex release from patch. Besides, the tape stripping test, attenuated total reflectance Fourier transform infrared (ATR-FTIR), and molecular simulation were carried out to elaborate the action of ion-pair on the Dex percutaneous permeation process. Results showed that the optimized patch prepared with Dex-salicylic acid (SA) showed zero-order skin permeation profile within 24 h; Dex-SA had greater hydrogen bonding formation potential with pressure sensitive adhesive (PSA) than Dex, which resulted in the decrease in the formation ability of free volume of PSA and the increase with the improvement of mechanical strength and chain stiffness of PSA and thus controlled the release rate of Dex from transdermal patch. Besides, the physicochemical properties of Dex such as molecular weight and octanol/water partition coefficient were changed after forming ion-pair with SA, which decreased the permeation ability of Dex. In conclusion, a controlled release drug-adhesive patch for Dex was developed and the mechanism study of ion-pair on the Dex release and percutaneous permeation process was proposed at molecular level.

Dexmedetomidine attenuates the neurotoxicity of propofol toward primary hippocampal neurons in vitro via Erk1/2/CREB/BDNF signaling pathways.

BACKGROUND: Propofol is a commonly used general anesthetic for the induction and maintenance of anesthesia and critical care sedation in children, which may add risk to poor neurodevelopmental outcome. We aimed to evaluate the effect of propofol toward primary hippocampal neurons in vitro and the possibly neuroprotective effect of dexmedetomidine pretreatment, as well as the underlying mechanism. MATERIALS AND PROCEDURES: Primary hippocampal neurons were cultured for 8 days in vitro and pretreated with or without dexmedetomidine or phosphorylation inhibitors prior to propofol exposure. Cell viability was measured using cell counting kit-8 assays. Cell apoptosis was evaluated using a transmission electron microscope and flow cytometry analyses. Levels of mRNAs encoding signaling pathway intermediates were assessed using qRT-PCR. The expression of signaling pathway intermediates and apoptosis-related proteins was determined by Western blotting. RESULTS: Propofol significantly reduced cell viability, induced neuronal apoptosis, and downregulated the expression of the BDNF mRNA and the levels of the phospho-Erk1/2 (p-Erk1/2), phospho-CREB (p-CREB), and BDNF proteins. The dexmedetomidine pretreatment increased neuronal viability and alleviated propofol-induced neuronal apoptosis and rescued the propofol-induced downregulation of both the BDNF mRNA and the levels of the p-Erk1/2, p-CREB, and BDNF proteins. However, this neuroprotective effect was abolished by PD98059, H89, and KG501, further preventing the dexmedetomidine pretreatment from rescuing the propofol-induced downregulation of the BDNF mRNA and p-Erk1/2, p-CREB, and BDNF proteins. CONCLUSION: Dexmedetomidine alleviates propofol-induced cytotoxicity toward primary hippocampal neurons in vitro, which correlated with the activation of Erk1/2/CREB/BDNF signaling pathways.

An improved ultra-high-performance liquid chromatography-tandem mass spectrometric method for the quantitation of dexmedetomidine in small volume of pediatric plasma.

Dexmedetomidine (Dex), a highly selective α2 -adrenergic agonist, is used primarily for the sedation and anxiolysis of adults and children in the intensive care setting. A sensitive and selective assay for Dex in pediatric plasma was developed by employing ultra-high-performance liquid chromatography-tandem mass spectrometry with d4-Dex as an internal standard. Dex was extracted from 0.1 mL of plasma by micro-elution solid-phase extraction. Separation was achieved with a Waters XBridge C18 column with a flow rate of 0.3 mL/min using a mobile phase comprising 5 mm ammonium acetate buffer with 0.03% formic acid in water and methanol-acetonitrile (50:50, v/v). The intra-day precision (coefficient of variation) and accuracy for quality control samples ranged from 1.32 to 8.91% and from 92.8 to 108%, respectively. The inter-day precision and accuracy ranged from 2.13 to 8.45% and from 97.0 to 104%, respectively. The analytical method showed excellent sensitivity using a small sample volume (0.1 mL) with a lower limit of quantitation of 5 pg/mL. This method is robust and has been successfully employed in a pharmacokinetic study of Dex in neonates and infants postoperative from cardiac surgery.

Dexmedetomidine protects against lipopolysaccharide-induced early acute kidney injury by inhibiting the iNOS/NO signaling pathway in rats.

Increasing evidence has demonstrated that dexmedetomidine (DEX) possesses multiple pharmacological actions. Herein, we explored the protective effect and potential molecular mechanism of DEX on lipopolysaccharide (LPS)-induced early acute kidney injury (AKI) from the perspective of antioxidant stress. We found that DEX (30 µg/kg, i.p.) ameliorated the renal dysfunction and histopathological damage (tubular necrosis, vacuolar degeneration, infiltration of inflammatory cells and cast formation) induced by LPS (10 mg/kg). DEX also attenuated renal oxidative stress remarkably in LPS-induced early AKI, as evidenced by reduction in production of reactive nitrogen species, decreasing malondialdehyde levels, as well as increasing superoxide dismutase activity and glutathione content. DEX prevented activator protein-1 translocation, inhibited phosphorylation of I-kappa B (IκB) and activation of nuclear factor kappa B (NF-κB) in LPS-induced early AKI, as assessed by real-time quantitative polymerase chain reaction and protein levels of c-Jun, c-Fos, IκB and NF-κB. Notably, DEX pretreatment had the same effect as intraperitoneal injection of an inhibitor of inducible nitric oxide synthase inhibitor (1400W; 15 mg/kg), and inhibited the activity of renal inducible nitric oxide synthase (iNOS) and decreased the expression of iNOS mRNA and NO production. However, the protective effect of DEX on LPS-induced early AKI was reversed by the alpha 2 adrenal receptor (α2-AR) inhibitor atipamezole, whereas the imidazoline receptor inhibitor idazoxan did not. Taken together, DEX protects against LPS-induced early AKI in rats by inhibiting the iNOS/NO signaling pathway, mainly by acting on α2-ARs instead of IRs.

Long-acting liposomal corneal anesthetics.

Eye drops producing long-acting ocular anesthesia would be desirable for corneal pain management. Here we present liposome-based formulations to achieve very long ocular anesthetic effect after a single eye drop instillation. The liposomes were functionalized with succinyl-Concanavalin A (sConA-Lip), which can bind corneal glycan moieties, to significantly prolong the dwell time of liposomes on the cornea. sConA-Lip were loaded with tetrodotoxin and dexmedetomidine (sConA-Lip/TD), and provided sustained release for both. A single topical instillation of sConA-Lip/TD on the cornea could achieve 105 min of complete analgesia and 608 min of partial analgesia, which was significantly longer than analgesia with proparacaine, tetrodotoxin/dexmedetomidine solution or unmodified liposomes containing tetrodotoxin and dexmedetomidine. sConA-Lip/TD were not cytotoxic in vitro to human corneal limbal epithelial cells or corneal keratocytes. Topical administration of sConA-Lip/TD provided prolonged corneal anesthesia without delaying corneal wound healing. Such a formulation may be useful for the management of acute surgical and nonsurgical corneal pain, or for treatment of other ocular surface diseases.

Long-acting hydrogel/microsphere composite sequentially releases dexmedetomidine and bupivacaine for prolonged synergistic analgesia.

Local anesthetics are a class of drugs, which have wide applications in the treatment of acute and chronic pain. However, their analgesic effects only last for a few hours because of their short half-life, which is insufficient for clinical application, especially for long-term surgery or postoperative analgesia. Herein, an injectable hydrogel/microsphere (GEL/MS) composite co-encapsulating bupivacaine (BUP) and dexmedetomidine (DEX) was developed for effective sustained analgesia. The GEL/MS composite appeared as a three-dimensional porous network microstructure and displayed sustained sequential release of DEX and BUP over several days in vitro, without obvious burst release. In this composite, DEX was released from the GEL matrix preferentially, exhibited long-term vasoconstriction effect and improved the local anesthetic concentration at injection site by preventing BUP from diffusing into the blood circulation. BUP was released subsequently from the MS for blockage of the Na+ channel on nerve cell membranes and provided long-term analgesia. In vivo analgesic effect demonstrated that DEX significantly prolonged the effect of analgesia when synergistically administered with BUP in the GEL/MS composite. Moreover, the GEL/MS composite exhibited good biodegradability and biocompatibility in histological analyses. Taken together, the administration of BUP and DEX in the GEL/MS composite achieved a synergistic effect in prolonging analgesia without causing toxicity, and thus represented a potential strategy for long-acting analgesia therapy.

Taurine enhances the protective effect of Dexmedetomidine on sepsis-induced acute lung injury via balancing the immunological system.

Sepsis, an overwhelming systemic inflammatory disease, is the leading cause of acute lung injury (ALI). Despite plenty of researches have been done, effective drugs treating septic ALI are still eagerly needed in the clinic. Dexmedetomidine (Dex), a potent alpha-2 adrenoreceptor agonist, has been reported to possess antioxidant, anti-apoptosis and anti-inflammatory abilities. Taurine, a kind of intracellular free amino acid, has been used to treat various diseases. This study aimed to explore the combination effect of Dex and Taurine on septic ALI and the underlying mechanism in vivo. The establishment of septic ALI was set up in SD rats by cecal ligation and puncture (CLP) operation. Results indicated that Dex or Taurine could reduce septic ALI-induced cell apoptosis via decreasing caspase-3 activity. However, the combination of Dex or Taurine produced greater effect. Besides that, Dex combined with Taurine could better promote cell proliferation with remarkably elevated Ki67 expression. The combination of Dex and Taurine significantly suppressed the activation of NF-κB pathway via inhibiting P65 phosphorylation and P65 nuclear translocation, leading to the down-regulation of interleukin (IL)-6 and IL-1ß. Moreover, co-administration of Dex and Taurine alleviated the imbalance of Th1/Th2 induced by septic ALI to a great extent. All in all, our study suggested the synergistic therapeutic effect of Dex and Taurine on septic ALI.

Quality by design-assisted development of a capillary electrophoresis method for the chiral purity determination of dexmedetomidine.

Dexmedetomidine is a selective α2 -adrenergic agonist used for patient sedation, while its enantiomer levomedetomidine has no sedative effects. As CE has been shown to be a powerful technique for enantiomer analysis, the aim of the study was the quality by design-based development of a CE-based limit test for the enantiomeric impurity levomedetomidine. The analytical target profile was defined that the method should be able to determine levomedetomidine with acceptable precision and accuracy at the 0.1% level. From initial scouting experiments, sulfated ß-cyclodextrin was selected as chiral selector. The critical process parameters were identified in a fractional factorial resolution V+ design, while a central composite face centered design and Monte Carlo simulations were used for defining the design space of the method. The selected working conditions were a 21.3/31.5 cm, 50 µm id fused-silica capillary, a 50 mM sodium phosphate buffer, pH 6.5, containing 40 mg/mL sulfated ß-cyclodextrin, a capillary temperature of 17°C and an applied voltage of 10 kV. Validation according to the ICH guideline Q2(R1) demonstrated repeatability and intermediate precision of content and migration time between 9.3 and 4.2% with accuracy in the range of 92.0 and 98.9%.

An improved liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of dexmedetomidine concentrations in samples of human plasma.

Dexmedetomidine (DMET) is a sedative, analgesic and anxiolytic with minimum adverse respiratory effects. An LC-MS/MS bioanalytical method has been developed and validated to accurately measure DMET concentrations in samples of human plasma. The method overcomes difficulties in the extraction and quantification of DMET due to the fact that it binds strongly to glass and plastic tubes, as well as solid phase extraction (SPE) cartridges. Human plasma (50 µL) was mixed with the internal standard (IS) (DMET-d4) solution (100 µL) and 0.1% formic acid (50 µL) and extracted using Oasis HLB 1 CC (30 mg) solid phase extraction (SPE) cartridges (Waters®). The glass tubes were coated with bovine serum albumin (BSA) 0.5% (20 µL) before eluting DMET and the IS. After evaporation under nitrogen at room temperature, the analytes were reconstituted in 20% acetonitrile in 0.1% formic acid in water and transferred to silanized glass vials. An electrospray ionisation (ESI) mass spectrometry method in positive mode was created and the precursor/product transitions (m/z) were 201.1 → 95.0 (DMET) and 204.9 → 99.0 (IS). The method was robust and fully validated based on the 2012 EMEA guideline for bioanalytical method validation in the concentration range of 0.5-20 ng/mL. Using this assay, we showed that DMET binds strongly to Extracorporeal Membrane Oxygenation (ECMO) circuits, consistent with expectations for small lipophilic compounds.

Stability of Dexmedetomidine in 0.9% Sodium Chloride in Two Types of Intravenous Infusion Bags.

Dexmedetomidine is a frequently used sedative in the critical care setting. It is commercially available as a 4-mg/mL premixed compound or as 200-mcg/2-mL vials that must be further diluted prior to administration. However, limited data exist regarding the stability of dexmedetomidine admixtures compounded from the 200-mcg/2-mL vials, particularly for durations greater than 48 hours. Therefore, we performed stability testing on compounded dexmedetomidine prepared in two types of intravenous infusion bags for 14 days. Dexmedetomidine is available as 200-mcg/2-mL vials for dilution, 80-mcg/20-mL single-dose vials, and as 200-mcg/50-mL and 400-mcg/100-mL glass bottles. The stability of dexmedetomidine admixtures has previously been tested for 48 hours. The purpose of this analysis was to test the stability of dexmedetomidine admixtures for 14 days. Six dexmedetomidine admixtures of 200 mcg/50 mL were compounded in polyvinyl chloride and non-polyvinyl chloride bags, three of which were stored under refrigeration and three of which were kept at room temperature. High-performance liquid chromatography testing was performed to determine the concentration at Days 1 through 14. Stability was determined by taking the mean concentration of samples taken from each bag. All samples were tested in duplicate. A sample was considered stable if the concentration was greater than 90% of the original concentration. All samples retained over 90% of the drug under their respective storage conditions for the duration of the study. At time 0, the concentration of dexmedetomidine was between 3.99 mcg/mL and 4.01 mcg/mL. On Day 14, the mean concentration was between 95.8% and 98.9%, depending on the bag type and storage condition. The pH remained between 4.7 and 5.8 during the study period as has previously been reported in the literature. Dexmedetomidine admixtures of 200 mcg/50 mL were stable in both polyvinyl chloride bags and non-polyvinyl chloride bags for 14 days under refrigeration and 48 hours at room temperature. This represents the longest time allowable under United States Pharmacopeia Chapter <797> without the need for sterility testing.

Multiply repeatable and adjustable on-demand phototriggered local anesthesia.

A phototriggerable system whereby patients could repeatedly and non-invasively control the timing and dosage of local anesthesia according to their needs would be beneficial for perioperative pain and perhaps obviate the need for oral narcotics. However, clinical application of phototriggerable systems have been limited by concerns over phototoxicity of lasers and limited tissue penetration of light. To address these limitations, we increased the devices' effective sensitivity to light by co-delivering a second compound, dexmedetomidine, that potentiates the effect of delivered local anesthetics. The concurrent release of dexmedetomidine enhanced the efficacy of released local anesthetics, greatly increasing the number of triggerable nerve blocks (up to nine triggerable events upon a single injection) and reducing the irradiance needed to induce nerve block by 94%. The intensity and duration of on-demand analgesia could be adjusted by varying the intensity and duration of irradiance, which could not only be delivered by lasers, but also by light-emitting diodes, which are less expensive, safer, and more portable.

Ultrasensitive Phototriggered Local Anesthesia.

An injectable local anesthetic producing repeatable on-demand nerve block would be desirable for pain management. Here we present a phototriggerable device to achieve repeatable and adjustable on-demand local anesthesia in superficial or deep tissues, consisting of gold nanorods attached to low temperature sensitive liposomes (LTSL). The particles were loaded with tetrodotoxin and dexmedetomidine. Near-infrared light (NIR, 808 nm, continuous wave) could heat gold nanorods at low fluence (short duration and low irradiance), leading to rapid release of payload. In vivo, 1-2 min of irradiation at ≤272 mW/cm2 produced repeatable and adjustable on-demand infiltration anesthesia or sciatic nerve blockade with minimal toxicity. The nerve block intensity and duration correlated with the irradiance and duration of the applied light.

Determination of dexmedetomidine in children's plasma by ultra-performance liquid chromatography tandem mass spectrometry and application to pharmacokinetic study.

A rapid, sensitive, and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of dexmedetomidine in children's plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2mL of acetonitrile to a 0.1mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.1min and the elution of dexmedetomidine was at 1.24min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring mode using the respective transitions m/z 201.3→95.1 for dexmedetomidine and m/z 204.2→98.0 for the internal standard, respectively. The calibration curve was linear over the range of 0.05-10ng/mL with a lower limit of quantitation of 0.05ng/mL. Mean recovery rate of dexmedetomidine in plasma was in the range of 86.7-89.1%. Intra-day and inter-day precision were both <11.6%. This method was successfully applied in pharmacokinetic study after commencement of 1.0µg/kg dexmedetomidine infusion in children.

Phototriggered Local Anesthesia.

We report a phototriggerable formulation enabling in vivo repeated and on-demand anesthesia with minimal toxicity. Gold nanorods (GNRs) that can convert near-infrared (NIR) light into heat were attached to liposomes (Lip-GNRs), enabling light-triggered phase transition of their lipid bilayers with a consequent release of payload. Lip-GNRs containing the site 1 sodium channel blocker tetrodotoxin and the α2-adrenergic agonist dexmedetomidine (Lip-GNR-TD) were injected subcutaneously in the rat footpad. Irradiation with an 808 nm continuous wave NIR laser produced on-demand and repeated infiltration anesthesia in the rat footpad in proportion to the irradiance, with minimal toxicity. The ability to achieve on-demand and repeated local anesthesia could be very beneficial in the management of pain.