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We studied the effect of the [[alpha].sub.2]-adrenergic receptor agonist clonidine hydrochloride ([10.sup.-9]-[10.sup.-6] M) on the isolated heart of adult rats after 30-day restriction of motor activity. In hypokinetic rats, in comparison with control animals, clonidine caused a positive inotropic effect; the dynamics of coronary flow was changed after stimulation of [[alpha].sub.2]-adrenergic receptors by clonidine in the minimum and maximum concentrations. Moreover, clonidine in concentrations of [10.sup.-8] and [10.sup.-7] M reduced coronary flow both in the control group and against the background of hypokinesia. Clonidine ([10.sup.-8]-[10.sup.-6] M) had a negative chronotropic effect in control and hypokinetic animals, while the dynamics of HR was multidirectional, i.e. either an increase or decrease in the effects was observed depending of the agonist concentration. Overall, the data obtained indicate the participation of [[alpha].sub.2]-adrenergic receptors in adaptive processes after motor activity limitation. Key Words: hypokinesia; isolated heart; rat; [[alpha].sub.2]-adrenergic receptors

We studied the effect of [[alpha].sub.2]-adrenoreceptor agonist clonidine hydrochloride in concentrations of [10.sup.-9] - [10.sup.-6] M on inotropy, chronotropy, and coronary flow in Langendorff-isolated heart of adult rats. It was found that [[alpha].sub.2]-adrenoreceptor agonist changed all studied parameters. Left ventricular myocardium contraction force decreased after application of all tested concentrations, the maximum effect was observed at a concentration of [10.sup.-6] M. Stimulation of [[alpha].sub.2]-adrenergic receptors in concentrations of [10.sup.-8], [10.sup.-7], and [10.sup.-6] M produced a two-phase effect (initial increase and a subsequent decrease) on the coronary flow. Clonidine hydrochloride in the maximum concentration ([10.sup.-6] M) caused a decrease in HR in one group and an increase in the other. Key Words: [[alpha].sub.2]-adrenergic receptors; chronotropy; inotropy; coronary flow; isolated heart

We studied the effect of [α.sub.2]-adrenoceptor stimulation with clonidine on BP and cardiac activity in rats. Variations in BP and chronotropism of the heart were studied in vivo after bolus injection of clonidine. In vitro experiments were performed to evaluate a dose-dependent change in myocardial contractility of the atria and ventricles after treatment with clonidine in concentrations of [10.sup.-9]-[10.sup.-5] M. [α.sub.2]-Adrenoceptor stimulation with clonidine had a negative chronotropic and inotropic effect and induced the decrease in systolic BP of rats. Key Words: heart; chronotropism; inotropy; blood pressure; rat

In this trial, clonidine, an α2-adrenergic agonist, did not reduce the rate of death or MI among patients undergoing noncardiac surgery. Clonidine did increase the risk of perioperative hypotension, bradycardia, and nonfatal cardiac arrest. Myocardial infarction is the most common major vascular complication of surgery and is associated with substantial mortality. 1 During and after noncardiac surgery, there is marked activation of the sympathetic nervous system, which can lead to a mismatch between the supply of and demand for myocardial oxygen and to subsequent myocardial infarction. 2 – 4 We previously reported that perioperative administration of a high-dose, long-acting beta-blocker (initiated 2 to 4 hours before surgery and continued after surgery) reduced the risk of myocardial infarction but increased the risk of death, stroke, and clinically important hypotension. 5 Clonidine, an α 2 -adrenergic agonist, blunts central sympathetic . . .

Background The α2 agonists, dexmedetomidine and clonidine, are used as sedative drugs during critical illness. These drugs may have anti-inflammatory effects, which might be relevant to critical illness, but a systematic review of published literature has not been published. We reviewed animal and human studies relevant to critical illness to summarise the evidence for an anti-inflammatory effect from α2 agonists. Methods We searched PubMed, the Cochrane library, and Medline. Animal and human studies published in English were included. Broad search terms were used: dexmedetomidine or clonidine, sepsis, and inflammation. Reference lists were screened for additional publications. Titles and abstracts were screened independently by two reviewers and full-text articles obtained for potentially eligible studies. Data extraction used a bespoke template given study diversity, and quality assessment was qualitative. Results Study diversity meant meta-analysis was not feasible so descriptive synthesis was undertaken. We identified 30 animal studies (caecal ligation/puncture (9), lipopolysaccharide (14), acute lung injury (5), and ischaemia-reperfusion syndrome (5)), and 9 human studies. Most animal (26 dexmedetomidine, 4 clonidine) and all human studies used dexmedetomidine. In animal studies, α2 agonists reduced serum and/or tissue TNFα (20 studies), IL-6 (17 studies), IL-1β (7 studies), NFκB (6 studies), TLR4 (6 studies), and a range of other mediators. Timing and doses varied widely, but in many cases were not directly relevant to human sedation use. In human studies, dexmedetomidine reduced CRP (4 studies), TNFα (5 studies), IL-6 (6 studies), IL-1β (3 studies), and altered several other mediators. Most studies were small and low quality. No studies related effects to clinical outcomes. Conclusion Evidence supports potential anti-inflammatory effects from α2 agonists, but the relevance to clinically important outcomes is uncertain. Further work should explore whether dose relationships with inflammation and clinical outcomes are present which might be separate from sedation-mediated effects.

The purpose of the current study was to develop tizanidine HCl (TIZ; a myotonolytic agent used for treatment of spasticity) loaded nanotransfersomes intended for rectal administration, aiming to bypass the hepatic first-pass metabolism. TIZ-loaded nanotransfersomes were prepared by thin-film hydration method followed by characterization for various parameters including entrapment efficiency, vesicle diameter, in vitro release and ex vivo permeation studies. Transfersomal formulation composed of phosphatidylcholine and Tween 80 at a weight ratio of (85:15) gave a satisfactory results. It exhibited encapsulation efficiency of 52.39%, mean diameter of 150.33 nm, controlled drug release over 8 h and good permeation characteristics. Optimum formula was then incorporated into Pluronic-based thermoreversible gel using hydroxypropyl methylcellulose (HPMC) as a mucoadhesive polymer. Pharmacokinetic study was performed by rectal administration of transfersomes-loaded in situ gel to rabbits and compared with oral drug solution and rectal TIZ in situ gel. The pharmacokinetic study revealed that the transfersomal formulation successively enhanced the bioavailability of TIZ by about 2.18-fold and increased t1/2 to about 10 h as compared to oral solution. It can be concluded that encapsulation of TIZ into nanotransfersomes can achieve a dual purpose of prolonged TIZ release and enhanced bioavailability and so may be considered as a promising drug delivery system for the treatment of spasticity.

PurposeDexmedetomidine increases sleep and reduces delirium in postoperative patients, but it is expensive and requires a monitored environment. Clonidine, another α2-agonist, is cheaper and is used safely for other purposes in wards. We assessed whether clonidine would improve sleep in postoperative high-dependency unit (HDU) patients.MethodsThe Clonidine at Low dosage postoperatively to Nocturnally Enhance Sleep (CLONES) study was a double-blind, placebo-controlled, parallel-group pilot effectiveness randomised trial involving adult elective surgery HDU patients in a single academic hospital. Patients received clonidine 0.3 μg/kg/h or saline placebo on the night of surgery. The primary outcome was total sleep time measured using a consumer actigraphy/photoplethysmography device.ResultsOf the 83 randomised patients, three had no data available, leaving 80 (39 clonidine, 41 placebo) in the intention-to-treat analysis, modified for missing data. Median patient ages of the groups were similar (61 and 59 years), as were other baseline characteristics. Clonidine patients had a mean of 100.8 (95% confidence interval [CI] 38.2–163.4) minutes (p = 0.002) longer total sleep time (mean 497.2 vs. 396.4 min) and reported better sleep overall. Delirium was only observed in one patient prior to study drug infusion, and none at the end of the study. Safety outcomes were not different. Four clonidine patients had their medication ceased due to bradycardia and hypotension that required no additional treatment.ConclusionAmong postoperative elective surgical patients admitted to HDU, low-dose non-titrated clonidine, compared to placebo, was associated with longer and subjectively better-quality sleep.

Objective To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). Background Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. Methods This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16–64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. Results Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (− 5.4, 5.8), p  = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p  = 0.012), there were no between-group differences in the secondary outcomes. Conclusion Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Background This systematic review and meta-analysis investigates the efficacy and safety of clonidine as a sedative in critically ill patients requiring invasive mechanical ventilation. Methods We performed a comprehensive search of MEDLINE, EMBASE, CINAHL and the Cochrane trial registry. We identified RCTs that compared clonidine to any non-clonidine regimen in critically ill patients, excluding neonates, requiring mechanical ventilation. The GRADE method was used to assess certainty of evidence. Results We included eight RCTs ( n  = 642 patients). In seven of the trials clonidine was used for adjunctive rather than stand-alone sedation. There was no difference in the duration of mechanical ventilation (mean difference (MD) 0.05 days, 95% confidence interval (CI) = -0.65 to 0.75, I 2  = 86%, moderate certainty), ICU mortality (relative risk (RR) 0.98, 95% CI = 0.51 to 1.90, I 2  = 0%, low certainty), or ICU length of stay (MD 0.04 days, 95% CI = -0.46 to 0.53, I 2  = 16%, moderate certainty), with clonidine. There was a significant reduction in the total dose of narcotics (standard mean difference (SMD) -0.26, 95% CI = -0.50 to -0.02, I 2  = 0%, moderate certainty) with clonidine use. Clonidine was associated with increased incidence of clinically significant hypotension (RR 3.11, 95% CI = 1.64 to 5.87, I 2  = 0%, moderate certainty). Conclusions Until further RCTs are performed, data remains insufficient to support the routine use of clonidine as a sedative in the mechanically ventilated population. Clonidine may act as a narcotic-sparing agent, albeit with an increased risk of clinically significant hypotension.