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.

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.

Stability of clonidine suspension in oral plastic syringes.

PURPOSE: The stability of clonidine suspensions stored at room temperature and under refrigeration for three months was evaluated. METHODS: Oral suspensions of clonidine 0.01 mg/mL were prepared in Ora-Blend and stored in clear plastic syringes at 25 °C and 4 °C. Samples were collected from each syringe at the time of preparation, at weekly intervals for up to 28 days, and on days 42, 56, 77, and 91. Changes in color, taste, and pH, as well as visual evidence of precipitation, were used to determine physical compatibility. Immediately after the physical observations were made, 1.5-mL samples from each syringe were transferred to polypropylene freezer vials and stored at -85 °C until high-performance liquid chromatographic (HPLC) analysis. The samples were analyzed by a validated stability-indicating HPLC-ultraviolet-light detection method. Stability was defined as the retention of at least 90% of the initial clonidine concentration. The precision of the assay was evaluated by intraday and interday validation methods. RESULTS: Clonidine suspensions stored at 25 °C and 4 °C maintained 99.2% and 99.0% of the initial concentration for 91 days, respectively. No interfering peaks were generated by forced degradation of clonidine with heat, hydrochloric acid, sodium hydroxide, or hydrogen peroxide There were no notable changes in pH, and all samples remained physically unchanged during the study period. CONCLUSION: An extemporaneously prepared suspension of clonidine 0.01 mg/mL in Ora-Blend was stable for at least 91 days when stored in clear plastic syringes at either 25 °C or 4 °C.

Melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine potentiate adrenergic receptor-mediated ocular hypotensive effects in rabbits: significance for combination therapy in glaucoma.

Melatonin is currently considered a promising drug for glaucoma treatment because of its ocular hypotensive and neuroprotective effects. We have investigated the effect of melatonin and its analog 5-methoxycarbonylamino-N-acetyltryptamine, 5-MCA-NAT, on ß2/α(2A)-adrenergic receptor mRNA as well as protein expression in cultured rabbit nonpigmented ciliary epithelial cells. Quantitative polymerase chain reaction and immunocytochemical assays revealed a significant ß2-adrenergic receptor downregulation as well as α(2A)-adrenergic receptor up-regulation of treated cells (P < 0.001, maximal significant effect). In addition, we have studied the effect of these drugs upon the ocular hypotensive action of a nonselective ß-adrenergic receptor (timolol) and a selective α2-adrenergic receptor agonist (brimonidine) in normotensive rabbits. Intraocular pressure (IOP) experiments showed that the administration of timolol in rabbits pretreated with melatonin or 5-MCA-NAT evoked an additional IOP reduction of 14.02% ± 5.8% or 16.75% ± 5.48% (P < 0.01) in comparison with rabbits treated with timolol alone for 24 hours. Concerning brimonidine hypotensive action, an additional IOP reduction of 29.26% ± 5.21% or 39.07% ± 5.81% (P < 0.001) was observed in rabbits pretreated with melatonin or 5-MCA-NAT when compared with animals treated with brimonidine alone for 24 hours. Additionally, a sustained potentiating effect of a single dose of 5-MCA-NAT was seen in rabbits treated with brimonidine once daily for up 4 days (extra IOP decrease of 15.57% ± 5.15%, P < 0.05, compared with brimonidine alone). These data confirm the indirect action of melatoninergic compounds on adrenergic receptors and their remarkable effect upon the ocular hypotensive action mainly of α2-adrenergic receptor agonists but also of ß-adrenergic antagonists.

An investigation about the inhibition of acute ischemia/reperfusion damage by dexmedetomidine in rat ovarian tissue.

Reperfusion has always been "the emergency intervention" to ischemic tissue. For a given period of time, tissue injury due to ischemia and reperfusion is more serious than injury due to ischemia only. Groups were as: Group 1: 25 µg/kg dexmedetomidine + ischemia/reperfusion group. Group 2: 10 mg/kg yohimbine +25 µg/kg dexmedetomidine + ischemia/reperfusion group. Group 3: Ischemia/reperfusion (control) group. Group 4: Healthy rats. Rat ovaries were exposed to a 3-hour ischemia and then reperfusion ensured for 2 hours. After ischemia/reperfusion, total glutathione, malondialdehyde, 8-hydroxyguanine levels and histopathological investigation were studied. The highest total glutathione and the lowest malondialdehyde and DNA damage levels were determined in dexmedetomidine group when compared to control group. The difference between yohimbine + dexmedetomidine and the control group was insignificant. Dexmedetomidine protects the ovarian tissue of the rat from I/R injury. It is hypothesized that this protective effect of dexmedetomidine is mediated by the α-2 adrenergic receptors. Dexmedetomidine could be useful for attenuation of tissue damage after I/R and prevention of I/R-related complications.

Quinoxaline derivatives: a patent review (2006--present).

INTRODUCTION: Quinoxaline scaffold is included in a large number of therapeutic agents because of its physicochemical properties that make the difference between them and the carbono analogue, naphthalene. AREAS COVERED: This review of patented products presents the quinoxaline heterocycle as part of the structural patent claims from a medicinal chemistry perspective. EXPERT OPINION: We centred our discussion in the various drug patent applications of the quinoxaline and its derivatives. The applications are based firstly in the specific enzyme target with very low development in the disease treatment. Only for cancer and antimicrobial agents they were specifically determined but little is mentioned in order to insight in the last development activities.

Stability of dexmedetomidine 4 µg/mL in polypropylene syringes.

PURPOSE: The results of a study to determine the long-term (up to 14 days) stability of diluted dexmedetomidine kept in polypropylene syringes under typical pharmacy storage conditions are presented. METHODS: Four samples of dexmedetomidine injection diluted to 4 µg/mL in 0.9% sodium chloride were prepared and divided into 25-mL portions for storage in syringes at ambient room temperature (20-25 °C) with light exposure or under refrigeration (5 °C) in darkness. At 24 and 48 hours, the percentage of the initial dexmedetomidine concentration remaining in all samples was assessed via high-performance liquid chromatography with diode-array detection; further stability testing of the refrigerated samples was performed on days 7 and 14. At each time point, the test samples were visually inspected for color, clarity, and signs of formation of particulate matter. RESULTS: As determined by chromatographic analyses, the samples of diluted dexmedetomidine stored in syringes at room temperature exhibited a loss of drug concentration of <10% over 48 hours; the refrigerated samples exhibited a loss of drug concentration of <5% over 14 days. All of the syringe-stored samples remained clear and colorless on visual inspection for the duration of the study. CONCLUSION: Dexmedetomidine diluted to 4 µg/mL in 0.9% sodium chloride injection was stable for at least 48 hours at 20-25 °C and 14 days at 5 °C when stored in polypropylene syringes.

Effects of crystalloid versus colloid and the α-2 agonist brimonidine versus placebo on intraocular pressure during prone spine surgery: a factorial randomized trial.

BACKGROUND: Volume replacement with colloid solution and topical α-2 agonists may each moderate the progressive increase in intraocular pressure (IOP) during prone surgery. The authors tested the hypotheses that during prolonged prone surgery, IOP increases less with goal-directed intravenous administration of 5% albumin than with goal-directed administration of lactated Ringer's solution, and with topical α-2 agonist brimonidine than with placebo eye drops. METHODS: Patients having complex prone spine surgery were factorially randomized to albumin and topical placebo (n = 15); albumin and topical brimonidine (n = 16); lactated Ringer's solution and topical placebo (n = 13); and lactated Ringer's solution and topical brimonidine (n = 16). IOP was measured with a pneumotonometer. The primary outcome was time-weighted average intraoperative IOP. RESULTS: Prone positioning increased IOP a mean ± SD of 12 ± 6 mmHg. IOP increased to 38 ± 10 mmHg at the end of anesthesia (approximately 5.5 h). Time- weighted average intraoperative IOP in the brimonidine group was 4 (95% CI: 1, 8) mmHg lower than in the placebo group (P = 0.023), but no different in the crystalloid and albumin groups (mean difference (95% CI) of -2 (-5, 2) mmHg (P = 0.34). There was no interaction between the two randomized factors. CONCLUSIONS: Brimonidine slightly reduced the primary outcome of intraoperative time-weighted average IOP, whereas there was no significant difference between goal-directed albumin or crystalloid administration. Brimonidine thus helps reduce IOP during spine surgery, but maintaining adequate blood pressure might play a more important role.

Biodegradable ocular inserts for sustained delivery of brimonidine tartarate: preparation and in vitro/in vivo evaluation.

The bioavailability of therapeutic agents from eye drops is usually limited due to corneal barrier functions and effective eye protective mechanisms. Therefore, the current study aims to enhance ocular bioavailability of brimonidine, a potent antiglaucoma drug, through the preparation of ocular inserts. Solvent casting technique was employed to prepare the inserts using polyvinylpyrrolidone K-90 (PVP K-90) as film-forming polymer blended with different viscosity grades of bioadhesive polymers namely hydroxypropyl methycellulose, carbopol, sodium alginate, and chitosan. The prepared ocular inserts were evaluated for various physicochemical parameters, swelling behavior, and in vitro release patterns. Sodium alginate-based ocular inserts revealed the most sustainment in drug release (99% at 6 h), so it was selected for further modifications via coating it, on one side or dual sides, using hydrophobic film composed of either ethylcellulose or Eudragit RSPO. The obtained in vitro release results for the modified ocular inserts revealed that ethylcellulose is superior to Eudragit RSPO in terms of brimonidine release sustainment effect. Ocular inserts composed of 7% PVP K-90, 1.5% low molecular weight sodium alginate with or without ethylcellulose coat were able to sustain the in vitro release of brimonidine. Their therapeutic efficacy regarding intraocular pressure (IOP) lowering effect when inserted in albino rabbits eyes showed superior sustainment effect compared with that of brimonidine solution. Furthermore, due to both the mucoadhesive property and the drug sustainment effect, the one-side-coated ocular insert showed more IOP lowering effect compared with that of its non-coated or dual-side-coated counterpart.