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Effective interventions to promote well-being at work are required to reduce the prevalence and consequences of stress and burnout especially during the COVID-19 pandemic. This study determined the effects of mindful coloring on perceived stress levels, mental well-being, burnout, and state and trait mindfulness levels for nurses during COVID-19.This was a single-center, two-armed, parallel, superiority, blinded randomized controlled trial. Seventy-seven participants were randomly allocated (by computer-generated sequence) to either mindful coloring (n = 39) or waitlist control groups (n = 38). Twenty-seven nurses in the mindful coloring group and 32 in the control group were included in the full compliance per protocol analysis. The mindful coloring intervention included participants viewing a 3-minutes instructional video and coloring mandalas for at least 5 working days or 100 minutes in total during a 10-day period. Participants in both groups completed the Perceived Stress Scale (total score 0-40), short Warwick-Edinburgh Mental Well-being Scale (total score 7-35), Maslach Burnout Inventory-Human Services Survey for Medical Personnel (3 subscales), Five Facets Mindfulness Questionnaire-Short Form (total score 24-120) and Mindful Attention Awareness Scale-State version (total score 0-30) instruments. The primary outcome was the perceived stress level.Baseline prevalence of moderate to high perceived stress level was high (79.2%). There was a large mindful coloring effect on reducing mean perceived stress levels (Mean difference [MD] in change between groups -3.0, 95% CI: -5.0 to -1.00; Cohen's d = 0.80). Mindful coloring may lead to a small improvement in mental well-being level (P = .08), with an improvement found in the intervention group (MD 0.9, 95% CI 0.0-1.8, P = .04) through enhanced state mindfulness (P .001). There were no effects on changing burnout subscales or trait mindfulness levels. No adverse reactions were reported.Coloring mandalas may be an effective low-cost brief intervention to reduce perceived stress levels through enhancing state mindfulness and it may promote mental well-being. Hospitals may promote or provide mindful coloring as a self-care and stress-relief practice for nurses during their off hours or work breaks.

Because nerve injury of muscles around the shoulder can be easily disguised by "trick movements" of the trunk, shoulder dysfunction following brachial plexus injury is difficult to quantify with conventional clinical tools. Thus, to evaluate brachial plexus injury and quantify its biomechanical consequences, we used inertial measurement units, which offer the sensitivity required to measure the trunk's subtle movements.We calculated 6 kinematic scores using inertial measurement units placed on the upper arms and the trunk during 9 functional tasks. We used both statistical and machine learning techniques to compare the bilateral asymmetry of the kinematic scores of 15 affected and 15 able-bodied individuals (controls).Asymmetry indexes from several kinematic scores of the upper arm and trunk showed a significant difference (P.05) between the affected and control groups. A bagged ensemble of decision trees trained with trunk and upper arm kinematic scores correctly classified all controls. All but 2 patients were also correctly classified. Upper arm scores showed correlation coefficients ranging from 0.55-0.76 with conventional clinical scores.The proposed wearable technology is a sensitive and reliable tool for objective outcome evaluation of brachial plexus injury and its biomechanical consequences. It may be useful in clinical research and practice, especially in large cohorts with multiple follow-ups.

SUMMARY STATEMENT Culture influences how we communicate, teach, and learn. Debriefings are laden with cultural influences. Without attention to cultural considerations, accepted debriefing techniques might not reach the desired outcome and, in certain cultures, may even harm teacher-learner relationships. We explore cultural considerations in healthcare simulation debriefing and offer guidance for debriefers to gain awareness of potential cultural biases.

OBJECTIVE This qualitative study was an integral part in the development of a multidisciplinary team-led school-based human papillomavirus vaccination health-promotion programme (MDL-SHPVP) aiming to increase HPV vaccine uptake in Hong Kong. Study findings will inform the design of the MDL-SHPVP by drawing on interview data regarding the expectations and needs of key stakeholders and potential programme users. METHODS Eight mother-daughter dyads, four secondary school teachers, two school principals, three social workers and one school nurse were interviewed. All interviews were audio-recorded and transcribed verbatim for thematic analysis. RESULTS Most participants had misconceptions about HPV and the vaccine. Alhough there was no immediate perceived need for the vaccination, most participants had favourable attitudes towards HPV inoculation and vaccines in general. Factors affecting vaccine uptake included perceptions about risk of infection, vaccine availability, and cost. Participants were largely open to suggested MDL-SHPVP components (videos, digital game, and group discussions). CONCLUSION Findings have highlighted knowledge gaps among potential users and key stakeholders and will be used to inform the design of the MDL-SHPVP to ensure that their needs and expectations are addressed. Study findings may also aid future HPV vaccine promotion efforts and boost HPV vaccine uptake among youth in the city.

BackgroundConversations are influenced by cultural perceptions, beliefs and values. Debriefing is a learning conversation. Without cross-cultural engagement or culturally relevant teaching, learning may be compromised and may result in an outcome opposite of that intended.ObjectiveThis systematic review explores cultural considerations in healthcare simulation debriefing. We sought to explore findings that could help debriefers create culturally responsive and inclusive debriefings.Study selectionStudies were included if they were peer-reviewed articles in any language and focused on healthcare simulation debriefing and global cultural considerations. Research study methods included qualitative, quantitative or both. The review included any health-related profession and level of learner.FindingsThree studies met the criteria. The purposes of the three studies were significantly different and did not directly study cultural considerations in debriefing.ConclusionsThe learner–educator relationship is at risk and learning may be negatively impacted without addressing cultural awareness. More studies are needed to fully describe the effect of culture on successful debriefing.

Introduction: Evidence has consistently shown the high efficacy of human papillomavirus (HPV) vaccines in preventing cervical cancers. However, the HPV vaccine uptake rate in Hong Kong is very low. We will develop and evaluate an innovative, theory-based multidisciplinary team-led school-based HPV vaccination health-promotion program (MDL-SHPVP), engaging female adolescents, parents/guardians, and secondary school personnel in multicomponent educational strategies and interactive discussions. Methods and analysis: A cluster randomized controlled trial is proposed. We will recruit 2520 female adolescents and their parents/guardians from 18 secondary day schools. The MDL-SHPVP is underpinned by the Health Belief Model and Precaution Adoption Process Model. Multicomponent interventions will be offered, including education sessions with small group dialogues with a registered nurse and trained healthcare and lay volunteers, and educational computer games. A team of volunteers will be established to raise HPV, cervical cancer, and HPV vaccine awareness. Outcomes include adolescents’ uptake of the HPV vaccine, adolescents’ intention to receive HPV vaccination, vaccine acceptance among parents/guardians, and parents’/guardians’ and adolescents’ HPV knowledge, attitudes, and beliefs. Data will be collected at baseline, 1 month, and 1 year after intervention. The generalized estimating equations analysis will be used for comparing the outcomes between the 2 groups. Ethics and dissemination: Ethical approval was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Ref. no.: 2019.055). We will disseminate the study findings via peer-reviewed publications and presentations at relevant events and international and local conferences. Trial registration number: ClinicalTrials.gov NCT04438291

Background Misplacement of the nasogastric tube in the respiratory tract could cause serious complications and even death. Thus, nasogastric tube verification is necessary for optimal patient safety and comfort. Although end-tidal carbon dioxide detection is considered an effective approach to determine nasogastric tube location, there is a paucity of up-to-date evidence. Objectives To review the diagnostic accuracy of end-tidal carbon dioxide detection in determining inadvertent airway intubation and verifying correct placement of nasogastric tubes. Design A systematic review and meta-analysis. Methods We searched clinical trials that evaluated the diagnostic accuracy of colorimetric capnometry or capnography in detecting nasogastric tubes located in the airway and differentiating between inadvertent airway intubation and correct nasogastric tube placement in any adult care setting. Four English language databases - Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and CINAHL - and four Chinese language databases - China Biomedical Literature Database, WanFang Data, China National Knowledge Infrastructure, and Airiti Library - were searched from July 2009 to March 2021. Clinical trial registration databases and reference lists of included studies and relevant reviews were also searched. Two reviewers extracted the data of all included studies using a data extraction form. Two reviewers assessed the methodological quality independently with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. We conducted meta-analysis using the hierarchical bivariate model and estimated the pool sensitivity and specificity of capnography and colorimetric capnometry. Forest plots were generated to display the results. Heterogeneity was investigated by meta-regression. The certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluations framework. Results Of 1,155 records identified, seven new studies were added to this update and a total of 16 studies were analysed in the systematic review. The total absolute number of true positive, false negative, true negative, and false positive observations were 142, 6, 1,500, and 65 respectively. Low to very low certainty of evidence indicated that the use of colorimetric capnometry or capnography is potentially an effective method in differentiating between respiratory and nasogastric tube placement for critically ill adult patients. Pooled results (13 studies, 1,541 intubations) for sensitivity and specificity were 0.96 (95% confidence interval [0.88, 0.99]) and 0.99 (95% confidence interval [0.96, 1.00]), respectively. Conclusions Colorimetric capnometry and capnography may have the potential to be of high sensitivity and specificity for the detection of inadvertent airway nasogastric tube placements in critically ill adults. More evidence is required to generalize the updated findings to different types of patients and settings.

Although there is consensus on the resuscitation of newborns, there is no standardization on how resuscitation equipment should be organized. This might lead to difficulty and inefficiency in retrieval of the right equipment during resuscitation. The neonatal resuscitation carts organized in accordance with the American Academy of Pediatrics (AAP) Neonatal Resuscitation Program (NRP) algorithm might result in more efficient retrieval of resuscitation equipment.To compare user preference and lengths of time required to retrieve standard resuscitation equipment from an NRP Cart versus a generic storage drawer.A prospective, randomized, controlled, and crossover trial was conducted during simulation-based NRP provider courses in the AccidentEmergency Training Centre from September to October 2013. The mean time of accurate equipment retrieval and ease of use, which was rated by the participants using a five-point Likert scale (1=most difficult, 5=easiest to use), were compared using the Wilcoxon signed-rank test because of right skew.A total of 55 individuals participated in this study. The mean length of time required for equipment retrieval from the NRP Cart was significantly less than that from the drawer (Z=-3.90, P0.01, median=36.23 s, interquartile range=97 s). In general, the NRP Cart was 32% faster than the drawer when extensive resuscitation equipment was required. All the participants rated the NRP Cart as easier to use than the drawer, with a median score of 4 for NRP Cart and 3 for the drawer (Z=-4.10, P0.01, interquartile range=2).The NRP Cart was superior to the generic drawer in terms of the speed of equipment retrieval and user acceptability.

Delivery and penetration of chemotherapeutic drugs into neoplasm through the tumor vasculature are essential mechanisms to enhance the efficiency of chemotherapy. "Vascular targeting" strategy focuses on promoting the infiltration of chemotherapeutic drugs into neoplastic tissues. In this study, we achieved a targeted therapy by coupling tumor necrosis factor α (TNFα) with TCP-1, a novel vascular-targeting peptide, in an orthotopic colorectal cancer model in mice. High dose of TCP-1-conjugated TNFα (TCP-1/TNFα: 5μg/mouse) displayed potent antitumor activity by inducing apoptosis and reducing microvessel number in tumors than unconjugated TNFα, with no evidence of increased toxicity. In the combined therapy, the antitumor action of 5-fluorouracil (5-FU) was potentiated when the mice were pretreated with a low dose of TNFα (1ng/mouse) and to a greater extent by the same concentration of TCP-1/TNFα. In this regard, TCP-1/TNFα combined with 5-FU synergistically inhibited the tumor growth, induced apoptosis and reduced cell proliferation. More importantly, TCP-1/TNFα normalized the tumor vasculature and facilitated the infiltration of immune cells to neoplasm as well as attenuated the immunosuppressing effects of TNFα in bone marrow and spleen. At the same time, TCP-1/TNFα significantly improved 5-FU absorption into the tumor mass. Taken together, these findings underscore the therapeutic potential of TCP-1 as a drug carrier in cancer therapy. TCP-1 is a novel vascular-targeting peptide and appears to be a promising agent for drug delivery. TCP-1 fused with TNFα holds great promise for colorectal cancer therapy.

Colorectal cancer (CRC) is the third most common malignancy and the fourth most frequent cause of cancer deaths worldwide. Ligand-mediated diagnosis and targeted therapy would have vital clinical applications in cancer treatment. In this study, an orthotopic model of colorectal cancer was established in mice. In vivo phage library selection was then utilized to isolate peptides specifically recognizing the vasculature of colorectal cancer tissues. A phage (termed TCP-1 phage) was isolated by this manner and it homed to the colorectal cancer tissues by 11- to 94-fold more than other organs. Chemical synthetic peptide (CTPSPFSHC, termed TCP-1) displayed by TCP-1 phage inhibited the homing ability of the phage to the tumor mass when co-injected intravenously with the TCP-1 phage into mice with colon cancer. Meanwhile, immunostaining analysis indicated that TCP-1 phage and peptide localized in the vasculature of the colorectal cancer tissue, but not of normal tissues. Moreover, TCP-1 peptide bound to blood vessels of surgical tissue samples of human colorectal cancer. After intravenous injection of FITC-labeled TCP-1 into the tumor-bearing mice for 20h, there was a strong fluorescent signal in the tumors but not other tissues when observed under blue light. In addition, TCP-1 conjugated with a pro-apoptotic peptide specifically induced apoptosis of tumor-associated blood vessels in vivo. The data define a novel peptide TCP-1 as an effective agent for imaging detection and drug delivery for colorectal cancer.

Background and purpose: Resveratrol, a naturally occurring polyphenolic antioxidant, has been shown to exhibit chemoprophylactic effects on cancer development. Previously, we reported that 2,3′,4,4′,5′-pentamethoxy-trans-stilbene (PMS), a methoxylated resveratrol derivative, exerted a highly potent anti-proliferative effect on human colon cancer cells as compared with its parent compound. In the present study, the chemopreventive effect of PMS was evaluated in a mouse model of colitis-associated colon carcinogenesis. Experimental approach: Seven-week-old Balb/c mice were injected i.p. with 10 mg·kg−1 azoxymethane (AOM). After 1 week, 3% dextran sodium sulphate (DSS) was administered in the drinking water for 7 days followed by 14 days of tap water for recovery, and this cycle was repeated twice. Key results: Intragastric administration of PMS (25, 50 mg·kg−1 body weight) for 16 weeks significantly reduced the multiplicity of colonic neoplasms by 15% and 35% (P < 0.01) respectively. Moreover, PMS at 50 mg·kg−1 inhibited colon cancer cell proliferation and promoted apoptosis. Such changes were accompanied by reduction of Akt (protein kinase B) phosphorylation, inactivation of β-catenin and down-regulation of inducible nitric oxide synthase. In parallel, in vitro studies also demonstrated that PMS inhibited proliferation and induced apoptosis in the murine colon adenocarcinoma cell line Colon26 with concomitant inhibition of Akt phosphorylation and inactivation of β-catenin. Conclusions and implications: PMS effectively suppressed colon carcinogenesis in an AOM/DSS animal model and may merit further clinical investigation as a chemoprophylactic agent against colitis-associated colon cancer in humans.

Aim of the study Dihydrotanshinone is a lipophilic component of the medicinal herb Salvia miltiorrhiza (danshen) belonging to the family of Labiatae. In this study, we have investigated the mechanisms of its relaxant effect on rat-isolated coronary artery. Materials and Methods Rat coronary artery rings were precontracted with 1 μM 5-hydroxytryptamine (5-HT). Involvement of endothelium-dependant mechanisms were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 μM), a nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 100 μM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a β-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9 H -purine-6-amine (SQ22536, 100 μM), a guanylyl cyclase inhibitor 1 H -[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ,10 μM), and a potassium channel inhibitor tetraethylammonium (TEA, 10 mM). Involvement of Ca 2+ channels was investigated in artery rings incubated with Ca 2+ -free buffer and primed with 1 μM 5-HT for 5 min prior to adding CaCl 2 to elicit contraction. Results Dihydrotanshinone relaxed the 5-HT-precontracted coronary artery rings with an IC50 value of 10.39 ± 1.69 μM. None of the above inhibitors or antagonists tested produced a significant change on the vasorelaxant effect of dihydrotanshinone, except ODQ caused a 50% reduction. Pre-incubation of the artery rings for 10 min with dihydrotanshinone (100 μM) abolished the CaCl 2 -induced vasoconstriction. Conclusions These findings suggest that inhibition of Ca 2+ influx in the vascular smooth muscle cells is important for the vasorelaxant effect of dihydrotanshinone, and it is independent of pathways involving the endothelium, muscarinic receptors, β-adrenoceptors, adenylyl cyclase, and guanylyl cyclase.

The antimicrobial peptide cathelicidin is critical for protection against different kinds of microbial infection. This study sought to elucidate the protective action of cathelicidin against Helicobacter pylori infection and its associated gastritis. Exogenous cathelicidin was found to inhibit H. pylori growth, destroy the bacteria biofilm, and induce morphological alterations in H. pylori membrane. Additionally, knockdown of endogenous cathelicidin in human gastric epithelial HFE-145 cells markedly increased the intracellular survival of H. pylori. Consistently, cathelicidin knockout mice exhibited stronger H. pylori colonization, higher expression of proinflammatory cytokines IL-6, IL-1β, and ICAM1, and lower expression of the anti-inflammatory cytokine IL-10 in the gastric mucosa upon H. pylori infection. In wild-type mice, H. pylori infection also stimulated gastric epithelium-derived cathelicidin production. Importantly, pretreatment with bioengineered Lactococcus lactis that actively secretes cathelicidin significantly increased mucosal cathelicidin levels and reduced H. pylori infection and the associated inflammation. Moreover, cathelicidin strengthened the barrier function of gastric mucosa by stimulating mucus synthesis. Collectively, these findings indicate that cathelicidin plays a significant role as a potential natural antibiotic for H. pylori clearance and a therapeutic agent for chronic gastritis.

This study investigates whether incomplete relaxation of vascular smooth muscle preparations induced by the prostacyclin analogue taprostene is due to partial agonism at prostanoid IP receptors. In the presence of the prostanoid EP4 receptor antagonist AH 23848, 3 microM taprostene induced 45% relaxation of phenylephrine-contracted guinea-pig saphenous vein rings and displaced log concentration-response curves for the prostacyclin analogues AFP-07, TEI-9063, and cicaprost to the right, parallel to their predicted addition curves. In contrast, taprostene interacted additively with prostaglandin E2 (PGE2), ONO-AE1-259 (selective EP2 agonist), and acetylcholine. Similarly, on rat tail artery contracted with phenylephrine, 3 microM taprostene (20% relaxation) opposed AFP-07- but not PGE2-induced relaxation. However, under U-46619-induced tone (AH 23848 absent), taprostene antagonized AFP-07 and cicaprost more than TEI-9063, suggesting that the latter has more than one relaxation mechanism. The presence of a sensitive EP3 contractile system in mouse aorta interfered with IP receptor-mediated relaxation. By generating tone with phenylephrine and the potent EP3 agonist sulprostone, it was possible to show that 3 microM taprostene (15% relaxation) selectively opposed relaxations induced by AFP-07, TEI-9063, and cicaprost. Our experiments indicate that taprostene is a partial agonist at prostanoid IP receptors, and may be a lead to an IP receptor antagonist.

1. Our study shows that the prostacyclin analogues AFP-07 and cicaprost are moderately potent agonists for prostanoid EP(4) receptors, in addition to being highly potent IP(1) receptor agonists. Both activities were demonstrated on piglet and rabbit saphenous veins, which are established EP(4) preparations. 2. On piglet saphenous vein, PGE(2) was 6.1, 24, 96, 138, 168 and 285 times respectively more potent than AFP-07, cicaprost, PGI(2), iloprost, carbacyclin and TEI-9063 in causing relaxation. Another prostacyclin analogue taprostene did not induce maximum relaxation (21 - 74%), and did not oppose the action of PGE(2). The EP(4) receptor antagonist AH 23848 (30 microM) blocked relaxant responses to PGE(2) (dose ratio=8.6+/-1.3, s.e.mean) to a greater extent than cicaprost (4.9+/-0.7) and AFP-07 (3.8+/-0.8), had variable effects on TEI-9063-induced relaxation (3.7+/-1.5), and had no effect on taprostene responses (

Contraction of guinea-pig isolated aorta induced by the prostaglandin E analogue sulprostone (1-400 nM) has a lower maximum response (40%) than that of phenylephrine or U-46619 (TP-receptor agonist). A prostanoid EP3-receptor subtype is involved based on agonist potency ranking: equi-effective molar ratios (EMR) are sulprostone (EC50 approximately equal to 23 nM) 1.0, SC-46275 0.11, misoprostol 2.2, gemeprost 3.3, PGE2 5.4, 17-phenyl PGE2 6.0, GR-63799 8.9. GR-63799, which contains a bulky ester group, is relatively more potent on neuronal EP3 preparations than on the aorta. ONO-AP-324, a relative of the non-prostanoid prostacyclin mimetic series, behaves as an EP3 partial agonist on the aorta, inhibiting sulprostone responses but acting synergistically (in a similar manner to sulprostone) with phenylephrine; it may be a useful pharmacological tool for studying EP3-receptors. Sulprostone contractions are markedly suppressed in zero-Ca2+ bathing fluid containing either 2 mM EDTA or 50 microM EGTA, and by Cd2+ (500 microM), but are usually unaffected by nifedipine (0.3 microM) and verapamil (4.44 microM). Influx of Ca2+, but not through L-type Ca2+-channels, appears to be the major contractile mechanism. The guinea-pig aorta is a valuable addition to the vascular EP3 preparations available and may increase our knowledge of the mechanisms whereby Gi-coupled receptors mediate vasoconstriction (c.f. 5-HT1B/D- and alpha2-receptors). The possibility of certain EP3 agonists distinguishing EP3-receptor isoforms is discussed.

219 surgical patients of either Caucasian, Chinese or Nepalese origin were given pethidine 1 mg/kg by intramuscular injection as pre-operative medication. Urine was collected for 24 h and analysed for pethidine, pethidinic acid, pethidinic acid conjugates, norpethidine, norpethidinic acid, and norpethidinic acid conjugates. The mean proportion of the percentage of metabolites attributable to oxidative demethylation, hydrolysis and conjugation was almost identical in each ethnic group (P>0.2). It was concluded that there were no differences in the metabolic variability of the biotransformation of pethidine in Asians and Caucasians in whom the urine pH had not been acidified.

A simple procedure for the simultaneous determination of flumazenil, midazolam, 1-hydroxymethylmidazolam and 4-hydroxymidazolam in plasma or urine in surgical patients is described. The assay involves a preliminary extraction of the drugs, metabolites and internal standard (flurazepam) from biological fluid into an organic solvent mixture (dichloromethane-diethyl ether, 40:60 v/v). The extract was evaporated to dryness at 40 degrees C under a gentle stream of nitrogen. The residue was re-dissolved in distilled methanol (80 microliters) and a 30-microliters aliquot was injected via an automatic sampler into the liquid chromatograph and eluted with the mobile phase (32% acetonitrile in 0.004 M sodium hydrogenphosphate buffer containing 1 ml of triethylamine and adjusted to pH 7.2) at a flow-rate of 1.5 ml/min on a 30-microns C8 precolumn linked to a 4-microns Nova-pak C18 cartridge column (100 mm x 8 mm I.D.) at ambient temperature (25 degrees C). The eluate was detected at 220 nm.

This review explores the significance of alpha-2 agonists used clinically in acute pain management.Although alpha-2 agonists have been reported to have an analgesic effect, they are not commonly used clinically for acute pain management. Clinical studies on use of alpha-2 agonists for acute pain management are reviewed and discussed. A literature search was done using Medline with the keywords 'alpha-2 agonist', 'clonidine', 'dexmedetomidine', 'fadolmidine', 'pharmacokinetics', 'pharmacodynamics', 'postoperative analgesia', 'epidural', 'intrathecal', 'peripheral nerve block' and various combinations with these keywords. The years 1977 - 2009 have been included, with particular focus on clinical studies from between 1990 and 2009.This article helps to clarify the clinical use of alpha-2 agonists in acute pain management according to current, up-to-date evidence. Clinically, available alpha-2 agonists, including clonidine and dexmedetomidine, are discussed in detail.Alpha-2 agonists, especially clonidine, seem to be promising with regard to acute postoperative pain management. However, more clinical evidence on dexmedetomidine is necessary to confirm its definite role in acute postoperative pain control.

Procedures based on gas chromatography were established to determine pethidine and its major metabolites in human urine. The chromatographic system consisted of a glass column packed with 3% (w/w) SP2250 on Chromosorb W (80–100 mesh) linked to a nitrogen—phosphorus detector. Diethyl ether was used as the extraction solvent. Pethidinic and norpethidinic acids, and their conjugated metabolites (after β-glucuronidase treatment) were determined after conversion into pethidine and norpethidine by acid-catalysed esterification. The retention times of pethidine, norpethidine and chlorpheniramine (internal standard) were 3.3, 4.5 and 7.5 min, respectively. The amount of unchanged drugs and metabolites excreted varied considerably among the subjects. The mean 24-h urinary recoveries in eight patients of pethidine, norpethidine, pethidinic acid, norpethidinic acid, and the glucuronides of pethidinic and norpethidinic acids were 6.62 ± 5.05, 4.33 ± 1.19, 18.9 ± 6.29, 9.10 ± 4.26, 15.1 ± 3.02 and 7.57 ± 2.28%, respectively. This indicates that the major metyabolic pathways of pethidine in the eight patients were hydrolysis followed by conjugation. Over 60% of the dose was accounted for in 24 h after intramuscular administration of 1 mg/kg pethidine.

In this study, we have investigated the actions of cryptotanshinone, an active, lipophilic component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the ethanol-extractable fraction of the herb. Extraction of the ethanol-soluble fraction from danshen provided a yield of 1%. The amount of cryptotanshinone determined in this ethanol extract was 3.682%, and it was 6 times more potent than the extract in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 2.65+/-0.15 microg/ml and 15.82+/-1.07 microg/ml, respectively. Involvement of endothelium-dependant mechanisms in their dilator effects were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium; none of these procedures produced a significant change on their dilator actions. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 100 mM); these also produced no change on their dilator actions. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT for 5 min prior to adding CaCl(2) to elicit contraction. The danshen ethanol extract (100 microg/ml) abolished the CaCl(2)-induced vasoconstriction, whereas, cryptotanshinone (30 microg/ml) produced 59% inhibition. These findings suggest their vasorelaxant effects are independent of pathways mediated by the endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase, whereas, inhibition of Ca(2+) influx in the vascular smooth muscle cells is important for their vasodilator actions. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen ethanolic extract suggest it is an important constituent in this medicinal herb.

In this study, we have investigated the mechanism of action through which salvianolic acid, a constituent of the medicinal herb danshen (Salvia miltiorrhiza), causes relaxation of isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT). The vasorelaxant effects of salvianolic acid B were also compared with the aqueous extract of danshen. Extraction of the water-soluble fraction from danshen provided a yield of 17.5%. The amount of salvianolic acid B determined in this aqueous extract was 3.9%, and the extract was 6.3 times less potent than salvianolic acid B in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 930.3+/-133.5 microg/ml and 147.9+/-17.4 microg/ml, respectively. Removal of the endothelium did not significantly affect their vasodilator potencies; IC(50) values were 842.1+/-123.8 mictog/ml and 160.3+/-25.9 microg/ml. On the other hand, a potassium channel inhibitor tetraethylammonium (TEA, 10 mM) shifted their concentration-response curves by 1.7 and 2.9 folds. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT or 60 mM KCl for 5 min prior to adding CaCl(2) to elicit contraction. In 5-HT-primed preparations, 2 mg/ml danshen aqueous extract and 0.72 mg/ml salvianolic acid B abolished the CaCl(2)-induced vasoconstriction, whereas, in KCl-primed preparations, 10 mg/ml danshen aqueous extract and 1.44 mg/ml salvianolic acid B produced 90% inhibition. These findings suggest the vasorelaxant effects of danshen aqueous extract and salvianolic acid B were produced by inhibition of Ca(2+) influx in the vascular smooth muscle cells. The opening of K(+) channels had a minor contribution to their effects, but endothelium-dependent mechanisms were not involved. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen aqueous extract suggest it is an important vasodilator constituent in this medicinal herb.

In this study, we have investigated the actions of danshensu, an active, water-extractable component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the water-extractable fraction of the herb. Extraction of the water-soluble fraction from danshen (S. miltiorrhiza) provided yield of 17.5% (35 g/200 g). The amount of danshensu determined in the crude danshen herb and in its aqueous fraction was 0.45 mg/g (0.045%) and 3.28 mg/g (0.33%). The danshen aqueous extract was 13 times less potent than danshensu in relaxing 5-HT-precontracted coronary artery rings; IC50 values were 930.3+/-133.5 microg/ml and 71.5+/-11.0 microg/ml. Removal of the endothelium did not significantly affect their vasodilator potencies; IC50 values were 842.1+/-123.8 microg/ml and 84.8+/-8.8 microg/ml. On the other hand, a potassium channel inhibitor tetraethylammonium (TEA, 10 mM) shifted their concentration-response curves by 1.7 and 2.2 folds. The possible involvement of Ca2+ channels was investigated in artery rings incubated with Ca2+-free buffer and primed with 1 microM 5-HT or 60 mM KCl for 5 min prior to addition of CaCl2 to elicit contraction. In 5-HT-primed preparations, the CaCl2-induced vasoconstriction was abolished by 2 mg/ml danshen aqueous extract and 200 microg/ml danshensu, whereas, in KCl-primed preparations, 10 mg/ml danshen aqueous extract and 600 microg/ml danshensu were required to abrogate the vasoconstriction. These findings suggest the vasorelaxant actions of danshen aqueous extract and danshensu were produced by inhibition of Ca2+ influx in the vascular smooth muscle cells. The opening of K+ channels had a minor contribution to the response, but endothelium-dependent mechanisms were not involved.

The possibility that the prostacyclin analogues AFP-07 and cicaprost relax saphenous vein preparations of pig, guinea-pig and rabbit by simultaneously activating prostanoid EP4 and IP (prostacyclin) receptors was investigated using the high-affinity EP4 antagonist GW 627368. The IP receptor system in each preparation was suppressed with the partial agonist taprostene. The results indicate that AFP-07 and cicaprost are moderately potent EP4 agonists on pig saphenous vein, but much weaker EP4 agonists on guinea-pig saphenous vein. GW 627368 did not antagonise AFP-07- and cicaprost-induced relaxation of rabbit saphenous vein, which contrasts with a previous study using the EP4 blocker AH 23848. However, treatment with taprostene was of less value due to poorer antagonism of the rabbit IP system; this may be related to the presence of a sensitive EP2 relaxant system. Relaxation of each preparation induced by the selective EP2 agonist ONO-AE1-259 was unaffected by GW 627368, with and without taprostene.

Prostacyclin stimulates sensory nerve endings or autonomic motor neurones in a number of tissues. Activation of prostacyclin (IP-) receptors appears to be involved since similar effects are produced by cicaprost (Figure 1), a highly potent and selective IP-receptor agonist (Dong et al., 1986). We have recently studied the actions of IP-receptor agonists on two isolated preparations, the rat colon and the guinea-pig vas deferens. In the former, cicaprost inhibits spontaneous contractile activity by releasing inhibitory transmitters from non-adrenergic non-cholinergic (NANC) enteric nerves (Qian and Jones, 1995). This action is partially inhibited by the nitric oxide synthase (NOS) inhibitor L-NAME (but not by D-NAME), indicating release of NO. The residual inhibition is abolished by apamin, indicating that a second transmitter probably activates receptors which open calcium-activated K+-channels in the pacemaker and/or smooth muscle cell membranes. The nature of this transmitter has not been defined, but it is unlikely to be adenosine, ATP, VIP (Qian and Jones, 1995) or PACAP (unpublished observations).

Danggui is a popular traditional Chinese medicinal (TCM) herb which is easily obtained by the public. The effects of Danggui on the pharmacokinetics and pharmacodynamics of warfarin were studied in rabbits. Single subcutaneous doses (2 mg/kg) of warfarin were administered to 6 rabbits with or without 3 days treatment with oral Danggui extracts (2 g/kg twice daily). Plasma warfarin concentrations were measured by high performance liquid chromatography (HPLC) for 72 h after each of the two warfarin doses. The prothrombin time (PT) was measured daily for 3 days both during the Danggui treatment period and after warfarin doses. Danggui treatment did not affect PT on its own, but significantly lowered PT values 3 days after co-treatment with single dose warfarin. No significant variations in the single dose pharmacokinetic parameters of warfarin were observed after Danggui treatment. A separate group of 6 rabbits were given daily subcutaneous doses of warfarin (0.6 mg/kg) to achieve steady state level, followed by 3 day treatment with oral Danggui extract (2 g/kg twice daily). The slight increase in PT was not significant and two rabbits died after day 7 of the treatment period. However, there was no significant difference in steady state concentrations of warfarin after the Danggui treatment. Results indicate that precautionary advice should be given to patients who self-medicate with Danggui or other TCM products while on chronic treatment with warfarin.

The method involves a single extraction of the drug and the internal standard, etidocaine, from alkalinized plasma with n-hexane. The gas chromatograph is equipped with a glass column (2.0 m x 2 mm) packed with 3% W/W SP2250 on Chromosorb W, (80/100 mesh) and a nitrogen sensitive detector. The method can accurately measure plasma bupivacaine concentrations down to 0.01 micrograms ml-1 using a sample size of 0.5 ml. The day-to-day variation of bupivacaine at 2.0 micrograms ml-1 is 6.90% (n = 10). The calibration graph is linear over the range 0.1-4.0 micrograms ml-1. The method is accurate, fast and sensitive and has been applied in a pharmacokinetic study of bupivacaine.

There are no selective agonists for the prostanoid EP4-receptor, and the ones available for the EP2-receptor are either of low potency (e.g. AH 13205) or are C1-methyl esters subject to variable de-esterification within tissues (e.g. butaprost). EP4 vasorelaxant systems are often highly sensitive, with IC50 values for PGE2 as low as 0.1 nM, whereas EP2 systems are usually some 30–100 times less sensitive. Determining whether EP2-receptors co-exist with EP4-receptors is therefore quite difficult. Some information can be gained using the EP4 antagonist AH 23848, but this blocker has a low affinity (pA2= 5.0–5.4), making large dose ratios difficult to obtain. We have recently investigated the utility of a new EP2 agonist, ONO-AE1-259 in this situation. ONO-AE1-259 (free acid) is claimed to be highly selective on the basis of radioligand competition and second messenger measurements on cloned mouse receptors; its EC50 for cyclic AMP production = 1.8 nM for EP2 and >10 μM for EP4-receptors (S. Narumiya; 11th International Conference on Prostaglandins, Florence, 2000). Rings of guinea-pig lateral saphenous vein were set up in a 4-channel Mulvaney myograph system (bath volume = 5 ml) in Krebs-Henseleit solution containing 1 μM indomethacin and 0.2 μM GR 32191 (TP antagonist). Tone was generated with 3 μM phenylephrine and agonists were added cumulatively. PGE2 induced ∼95% relaxation at 5 nM and had an EC50 of about 0.1 nM. ONO-AE1-259 consistently showed small relaxant effects at 1 nM, but its log concentration-response curve was shallower than that of PGE2 and only about 85% relaxation was found at 5 μM (IC50= 20 nM relative to its own maximum). The vein preparation did not contact to sulprostone, and therefore is unlikely to contain opposing EP1 and/or EP3 systems. In the presence of 30 μM AH 23848, the log concentration-response curve for PGE2 was displaced to the right in a parallel manner (dose ratio = 7.6, pA2= 5.3). However, the ONO-AE1-259 curve was only slightly displaced to the right by AH 23848 (dose ratio = 1.6), while at the same time maximum relaxation was reduced by 15%. ONO-AE1-259 was about 25 times more potent than butaprost. It is possible therefore that ONO-AE1-259 is selectively activating a relaxant EP2-receptor in the guinea-pig saphenous vein. The saphenous vein preparation is also highly sensitive to the prostacyclin analogues AFP-07 (IC50= 0.65 nM) and cicaprost (IC50= 7 nM). We are investigating whether these analogues activate IP and/or EP4 receptors, in the light of our recent finding that they are potent and moderately potent EP4 agonists respectively on both piglet and rabbit saphenous veins (Jones & Chan, 2001, Br. J. Pharmacol., in press).