The burden of musculoskeletal pain, associated sociodemographic factors, and disability in Pakistan.

OBJECTIVE: The objective of this survey was to determine the burden of musculoskeletal (MSK) pain, its association with sociodemographic factors and disability in the semi-urban community of Nain-Sukh, Lahore. METHODS: The current article's data is taken from the COPCORD survey conducted in the community of Nain-Sukh. After formal IRB approval, data collection was done via interview by a trained team using validated Urdu translation of COPCORD core questionnaires. Participants of both genders, >16 years, were enrolled through a random walk and quota sampling. In phase 1, sociodemographic factors were recorded. In phase 2, the impact of MSK pain on functional disability was assessed by the Modified Health Assessment Questionnaire (MHAQ). The data was compiled and analyzed using software SPSS version 25. The Chi-square test was applied to determine association while generalized linear regression models to see the dependence of sociodemographic factors and MSK pain. RESULTS: Out of 4922 participants, 1425 (28.9%) had MSK pain, with a mean age of 35 ± 14 years, with female predominance. Illiteracy, marital status, and household work with moderate intensity were significantly associated with MSK pain. Based on the MHAQ score, the majority 769 (82.9%) had a mild disability. Odds of advancing age, illiteracy, and moderate intensity of work were statistically significant for MSK pain. CONCLUSION: Every fourth subject in the surveyed population had MSK pain. Musculoskeletal pain was found to be significantly associated with female gender, advancing age, household work, illiteracy, married status, and moderate nature of work. More than two-thirds of the subjects with MSK pain had some degree of disability.

Treatment of spinal anaesthesia-induced hypotension with cafedrine/theodrenaline versus ephedrine during caesarean section: Results from HYPOTENS, a national, multicentre, prospective, noninterventional study.

BACKGROUND: In Germany, hypotension induced by spinal anaesthesia is commonly treated with a combination of cafedrine hydrochloride (C, 200 mg) and theodrenaline hydrochloride (T, 10 mg) in 2 ml. We compared the effectiveness of C/T with ephedrine. OBJECTIVES: The primary objectives were to assess the speed of onset and the ability to restore blood pressure without an increase in heart rate. Secondary objectives were to evaluate maternal/foetal outcomes and the number of required additional boluses or other additional measures. DESIGN: HYPOTENS was a national, multicentre, prospective, open-label, two-armed, noninterventional study comparing C/T with ephedrine in two prospectively defined cohorts. This study relates to the cohort of patients receiving spinal anaesthesia for caesarean section. SETTING: German hospitals using either C/T or ephedrine in their routine clinical practice. PATIENTS: Women aged at least 18 years receiving spinal anaesthesia for caesarean section. INTERVENTIONS: Bolus administration of C/T or ephedrine at the discretion of the attending anaesthesiologist. MAIN OUTCOME MEASURES: Endpoints within 15 min after initial administration of C/T or ephedrine were area under the curve between the observed SBP and the minimum target SBP; and incidence of newly occurring heart rate of at least 100 beats min-1. RESULTS: Although effective blood pressure stabilisation was achieved with both treatments, this effect was faster and more pronounced with C/T (P < 0.0001). The incidence of tachycardia and changes in heart rate were higher with ephedrine (P < 0.01). Fewer additional boluses (P < 0.01) were required with C/T. Although favourable neonatal outcomes were reported in both groups, base deficit and lactate values were greater with ephedrine (P < 0.01). Physician satisfaction was higher with C/T. CONCLUSIONS: After C/T, tachycardia was not a problem, providing an advantage over ephedrine. Fewer additional boluses were required with C/T, suggesting greater effectiveness. An increased base deficit with ephedrine suggests reduced oxygen supply or increased demands in foetal circulation. TRIALS REGISTRATION: Clinicaltrials.gov: NCT02893241, German Clinical Trials Register: DRKS00010740.

Treatment of intraoperative hypotension with cafedrine/theodrenaline versus ephedrine : A prospective, national, multicenter, non-interventional study-the HYPOTENS trial.

BACKGROUND: Sympathomimetic drugs are a therapeutic cornerstone for the management of hypotensive states like intraoperative hypotension (IOH). While cafedrine/theodrenaline (C/T) is widely used in Germany to restore blood pressure in patients with IOH, more research is required to compare its effectiveness with alternatives such as ephedrine (E) that are more commonly available internationally. METHODS: HYPOTENS (NCT02893241, DRKS00010740) was a prospective, national, multicenter, open-label, two-armed, non-interventional study that compared C/T with E for treatment of IOH. We describe a prospectively defined cohort of patients ≥50 years old with comorbidities undergoing general anesthesia induced with propofol and fentanyl. Primary objectives were to examine treatment precision, rapidity of onset and the ability to restore blood pressure without relevant increases in heart rate. Secondary endpoints were treatment satisfaction and the number of required additional boluses or other accompanying measures. RESULTS: A total of 1496 patients were included in the per protocol analysis. Overall, effective stabilization of blood pressure was achieved with both C/T and E. Post-hoc analysis showed that blood pressure increase from baseline was more pronounced with C/T. Fewer additional boluses or other accompanying measures were required in the C/T arm. The incidence of tachycardia was comparable between groups. Post-hoc analysis showed that E produced dose-dependent elevated heart rate values. By contrast, heart rate remained stable in patients treated with C/T. Physicians reported a higher level of treatment satisfaction with C/T, with a higher proportion of anesthetists rating treatment precision and rapidity of onset as good or very good when compared with E. CONCLUSION: Neither drug was superior in restoring blood pressure levels; however, post-hoc analyses suggested that treatment is more goal-orientated and easier to control with C/T. Heart rate was shown to be more stable with C/T and fewer additional interventions were required to restore blood pressure, which could have contributed to the increased treatment satisfaction reported by anesthetists using C/T.

Norepinephrine as new functional monomer for molecular imprinting: An applicative study for the optical sensing of cardiac biomarkers.

The continuous research for alternatives to antibody-based detection drove, in the last decades, the development of numerous strategies. Molecularly imprinted polymers (MIPs) emerged thanks to the low-cost and long-term stability features, where the choice of natural functional monomer(s) represents the key step for efficient imprinting of biomolecules. The chemical structure of dopamine (DA), one of the most used natural functional monomers, provided the inspiration for this work. We wondered why norepinephrine (NE) that differs from dopamine only for an additional hydroxyl group was not investigated at all in biosensing applications. In fact, there is only one paper exploiting polynorepinephrine (PNE) in molecular recognition applications, taking advantage of molecular imprinting, but not for biosensing purposes. In contrast, hundreds of papers describe polydopamine-based sensors. Therefore, we firstly investigated how the additional hydroxyl group of NE could affect the properties of the resulting polymer, and how these properties could be exploited for biosensing applications. The results highlighted the reduced non-specific adsorption of proteins onto PNE with respect to dopamine polymer. Furthermore, as a case study, we successfully developed a PNE-based imprinted biosensor for the early detection of Troponin I, a crucial biomarker for heart failure, by coupling the MIP biosensor with surface plasmon resonance (SPR) detection. The results indicate the feasible use of imprinted PNE as synthetic receptor for biomolecules, opening new perspectives for this biopolymer, so far not considered, and encouraging further investigations on its potential application in biosensing.

Enantioseparation of chiral ß-blockers using polynorepinephrine-coated nanoparticles and chiral capillary electrophoresis.

A method of combining magnetic solid-phase separation (MSPE) and chiral capillary electrophoresis (CE) is developed for enantioseparation of trace amounts of ß-blockers. Polynorepinephrine-functionalized magnetic nanoparticles (polyNE-MNPs) are synthesized and applied to simultaneously extract three ß-blockers (carteolol, metoprolol, and betaxolol). The prepared polyNE-MNPs are spherical with a diameter of 198 ± 17 nm and the thickness of the polyNE coating is about 14 nm. PolyNE possesses abundant catechol hydroxyl and secondary amine groups, endowing the MNPs with excellent hydrophilicity. Under the optimum conditions, the extraction efficiencies of polyNE-MNPs for ß-blockers are in the range of 89.6 to 100%, with relative standard deviations (RSDs) below 3.5%. The extraction process can be finished in 4 min. Field-enhanced sample injection (FESI) in chiral CE is constructed to further enhance the sensitivities of ß-blocker enantiomers. The limits of detection for ß-blocker enantiomers by the FESI-CE with polyNE-MNPs are in the range of 0.401 to 1.59 ng mL-1. The practicability of this method in real samples is evaluated by analysis of human urine samples. The recoveries for each enantiomer of ß-blockers in the real samples range from 89.5 to 92.8%, with RSDs ranging from 0.37 to 5.9%. The whole detection process can be finished in less than 0.5 h. The method demonstrates its great potential in the pharmacokinetic and pharmacodynamic studies of chiral drugs in humans. Graphical abstract ᅟ.

Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.

In intensive care, drugs are commonly administered through central venous catheters (CVC). These catheters and central venous dialysis catheters (CVDC) are often placed in the same vessel for practical reasons. The aim of this experimental study was to investigate if the position of CVC and CVDC influences the elimination of infused drugs, during continuous renal replacement therapy (CRRT). In a randomized, cross-over model, anesthetized piglets received both a CVC and a CVDC in a jugular vein. Another CVDC was placed in a femoral vein for comparison. After baseline measurements, CRRT was performed in either of the CVDC, each CRRT-period separated by another baseline period. Hypotension was induced by peripherally given sodium nitroprusside. In the CVC, both gentamicin and noradrenaline were administered. Noradrenaline was titrated to reach a target blood pressure. When CRRT was performed using the CVDC in the same vessel as the drugs were infused, the plasma concentration of gentamicin was reduced compared with when the infusion and CVDC were in different vessels (5.66 [standard deviation (SD) ± 1.23] vs. 7.76 [SD ± 2.30] mg/l [p = 0.02]). The noradrenaline infusion rate needed to reach the target blood pressure was more than doubled (0.32 [SD ± 0.16] vs. 0.15 [SD ± 0.08] µg/kg/min [p = 0.006]). This experimental study indicates that the removal of drugs is increased if infusion is in close vicinity of the CVDC, during CRRT.

Identifying binding modes of two synthetic derivatives of adrenalin to the α2C-adrenoceptor by using molecular modeling; insights into the α2C-adrenoceptor activation.

Although, α2C adrenergic receptor (AR) mediates a number of physiological functions in vivo and has great therapeutic potential, the absence of its crystal structure is a major difficulty in the activation mechanism studies and drug design endeavors. Here, a homology model of α2C AR has been presented by means of multiple sequence alignment. The used templates were the latest crystal structures of the other ARs (Protein Data Bank IDs: 2R4R, 2RH1, 4GPO, 3P0G, 4BVN and 4LDO) that have 38.4% identity with the query. We then conducted docking simulations to understand and analyze the binding of noradrenaline (NOR), and its derivatives, namely arachidonoyl adrenalin (AA-AD) and arachidonoyl noradrenalin (AA-NOR) to the receptor. The existence of H-bonds between the ligands and SER218 residue implies the same binding site of derivatives with respect to the NOR. AA-AD and AA-NOR bind to the receptor with the larger binding affinities. The presence of salt bridge between ARG149 and GLU377 in the free receptor, obtained from molecular dynamics studies proved that the receptor still is in its basal state before binding process take places. The activation process is characterized by increasing in the RMSD values of the backbone receptor in the bound state, increasing the RMSF of the transmembrane involved in the activation process and the disappearance of the ARG149-GLU377 salt bridge.

Binding assessment of two arachidonic-based synthetic derivatives of adrenalin with ß-lactoglobulin: Molecular modeling and chemometrics approach.

A computational approach to predict the main binding modes of two adrenalin derivatives, arachidonoyl adrenalin (AA-AD) and arachidonoyl noradrenalin (AA-NOR) with the ß-lactoglubuline (BLG) as a nano-milk protein carrier is presented and assessed by comparison to the UV-Vis absorption spectroscopic data using chemometric analysis. Analysis of the spectral data matrices by using the multivariate curve resolution-alternating least squares (MCR-ALS) algorithm led to the pure concentration calculation and spectral profiles resolution of the chemical constituents and the apparent equilibrium constants computation. The negative values of entropy and enthalpy changes for both compound indicated the essential role of hydrogen bonding and van der Waals interactions as main driving forces in stabilizing protein-ligand complex. Computational studies predicted that both derivatives are situated in the calyx pose and remained in that pose during the whole time of simulation with no any significant protein structural changes which pointed that the BLG could be considered as a suitable carrier for these catecholamine compounds.

Beta-adrenergic receptor agonist decreases VEGF levels through altered eNOS and PKC signaling in diabetic retina.

Vascular endothelial cell growth factor (VEGF) is increased in diabetic macular edema. Compound 49b, a novel ß-adrenergic receptor agonist, is protective in a type 1 diabetic rat model. We questioned whether Compound 49b could decrease VEGF levels, suggesting that Compound 49b may be effective against edema. Two-month diabetic rats received topical Compound 49b for 7 days only and/or insulin-like growth factor binding protein 3 (IGFBP-3) siRNA. We also measured endothelial nitric oxide synthase (eNOS) and protein kinase C (PKC)ζ and PKCδ phosphorylation. Retinal endothelial cells (RECs) cultured in high glucose were treated with Compound 49b and IGFBP-3 siRNA for evaluation of the same signaling pathways. Compound 49b significantly decreased VEGF through increased IGFBP-3 in the diabetic retina. Compound 49b also reduced eNOS, PKCζ and PKCδ phosphorylation in the diabetic retina and REC. Compound 49b regulated a number of proteins involved in REC barrier properties.

Effects of atomoxetine on attention and impulsivity in the five-choice serial reaction time task in rats with lesions of dorsal noradrenergic ascending bundle.

Atomoxetine, a noradrenaline reuptake inhibitor (NRI), which is a non-stimulating medicine that is used for the treatment of patients with attention deficit hyperactivity disorder (ADHD), has been found to be effective in reducing behavioral impulsivity in rodents, but its efficacy in a dorsal noradrenergic ascending bundle (DNAB)-lesioned condition has not been examined. The present study aimed to investigate the effects of DNAB lesions on attention and impulsive control in the five-choice serial reaction time task (5-CSRTT) in rats treated with atomoxetine. The drug-induced changes in noradrenaline efflux in the medial prefrontal cortex were also measured. 5-CSRTT-trained rats were included in one of the following groups: N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)/Atomoxetine, Sham/Atomoxetine, DSP-4/Saline, or Sham/Saline. Acute atomoxetine (0.3 mg/kg) was administered 14 days after the DSP-4 regime. The behavioral testing included manipulations of the inter-trial interval (ITI), stimulation duration and food satiety. In vivo microdialysis of the noradrenaline efflux in the medial prefrontal cortex and the expression of the noradrenaline transporter (NAT) in the DNAB areas were examined. Atomoxetine reduced impulsivity and perseveration in the long-ITI condition with no effects on any other variables. This phenomenon was not influenced by DSP-4 pre-treatment. The DNAB-lesioned rats had lower noradrenaline efflux in the medial prefrontal cortex. DSP-4 caused no change in NAT expression in the DNAB areas. These findings suggested that noradrenaline reuptake may not be exclusively responsible for the atomoxetine effects in adjusting impulsivity. The role of DNAB should also be considered, particularly in conditions requiring greater behavioral inhibition.

Dopamine antagonism decreases willingness to expend physical, but not cognitive, effort: a comparison of two rodent cost/benefit decision-making tasks.

Successful decision making often requires weighing a given option's costs against its associated benefits, an ability that appears perturbed in virtually every severe mental illness. Animal models of such cost/benefit decision making overwhelmingly implicate mesolimbic dopamine in our willingness to exert effort for a larger reward. Until recently, however, animal models have invariably manipulated the degree of physical effort, whereas human studies of effort have primarily relied on cognitive costs. Dopamine's relationship to cognitive effort has not been directly examined, nor has the relationship between individuals' willingness to expend mental versus physical effort. It is therefore unclear whether willingness to work hard in one domain corresponds to willingness in the other. Here we utilize a rat cognitive effort task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, and a previously established physical effort-discounting task (EDT) to examine dopaminergic and noradrenergic contributions to effort. The dopamine antagonists eticlopride and SCH23390 each decreased willingness to exert physical effort on the EDT; these drugs had no effect on willingness to exert mental effort for the rCET. Preference for the high effort option correlated across the two tasks, although this effect was transient. These results suggest that dopamine is only minimally involved in cost/benefit decision making with cognitive effort costs. The constructs of mental and physical effort may therefore comprise overlapping, but distinct, circuitry, and therapeutic interventions that prove efficacious in one effort domain may not be beneficial in another.

Covalent agonists for studying G protein-coupled receptor activation.

Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the ß2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis.

A sensitive and fast LC-MS/MS method for determination of ß-receptor agonist JP-49b: application to a pharmacokinetic study in rats.

Ocular administration of the beta (ß)-adrenergic receptor agonist JP-49b prevents retinopathy-like damage in a preclinical rat model of diabetes. Importantly, JP-49b did not induce characteristic ß-adrenergic agonist-related side effects (e.g., left ventricular damage), which led to the hypothesis that JP-49b systemic exposure was minimal following ocular administration. To test this hypothesis, a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to study the preclinical pharmacokinetics of JP-49b in rats. Animals received either a single periocular or intravenous injection of JP-49b (10mg/kg) and plasma and tissue samples were obtained. JP-49b and fenoterol hydrobromide (internal standard, IS) were isolated by liquid-liquid extraction and extracts were analyzed by reversed-phase liquid chromatography on a C18 column using a gradient elution (acetic acid in water and methanol). A triple quadrupole mass spectrometer operating in the positive electrospray ionization mode with multiple reaction monitoring was used to detect JP-49b and IS transitions of m/z 346.4→195.1 and 304.1→134.9. The method was validated for selectivity, linearity, accuracy, and precision in rat vitreous humor, tissue homogenates, and plasma. Following intravenous administration, JP-49b was found to have a rapid clearance (36±5.8L/h/kg), high volume of distribution (244±51.5L/kg) and a terminal half-life of 4.8±1.6h. JP-49b was rapidly absorbed and extensively distributed into ocular tissue following topical administration. However, JP-49b was undetectable in heart tissue 24h after ocular administration. High local drug concentrations coupled with minimal systemic exposure following ocular administration supports further testing of JP-49b as a localized therapy for diabetic retinopathy.

Modulation of the perforant path-evoked potential in dentate gyrus as a function of intrahippocampal ß-adrenoceptor agonist concentration in urethane-anesthetized rat.

BACKGROUND: ß-adrenoceptor activation in the hippocampus is sufficient to induce heterosynaptic long-term potentiation of perforant path input to the dentate gyrus. However, in vitro and in vivo studies suggest the plasticity effects of ß-adrenoceptor activation may vary depending on the level of receptor activation. METHODS: The present experiments use an in vivo model concurrently infusing differing concentrations of the ß-adrenoceptor agonist, isoproterenol (ISO; 0, 0.1, 1, 10, and 100 µmol/L in aCSF; 1 µL over 12.5 min) in the dentate gyrus, while monitoring changes in the perforant path-evoked potential at the same site. RESULTS: Long-term depression (LTD) of fEPSP slope was elicited by 0.1 µmol/L ISO. Higher doses did not alter fEPSP slope. Maximal long-term potentiation of the perforant path-evoked population spike (183% >3 h) occurred at 10 µmol/L ISO. Transient depression of spike amplitude occurred at 0.1 µmol/L ISO. CONCLUSIONS: These data demonstrate concentration-dependent effects of ß-adrenoceptor activation on the perforant path-evoked potential. Long-term depression and long-term potentiation of perforant path-evoked responses are variably elicited as a function of the degree of receptor activation.

Simulations of biased agonists in the ß(2) adrenergic receptor with accelerated molecular dynamics.

The biased agonism of the G protein-coupled receptors (GPCRs), where in addition to a traditional G protein-signaling pathway a GPCR promotes intracellular signals though ß-arrestin, is a novel paradigm in pharmacology. Biochemical and biophysical studies have suggested that a GPCR forms a distinct ensemble of conformations signaling through the G protein and ß-arrestin. Here we report on the dynamics of the ß2 adrenergic receptor bound to the ß-arrestin and G protein-biased agonists and the empty receptor to further characterize the receptor conformational changes caused by biased agonists. We use conventional and accelerated molecular dynamics (aMD) simulations to explore the conformational transitions of the GPCR from the active state to the inactive state. We found that aMD simulations enable monitoring of the transition within the nanosecond time scale while capturing the known microscopic characteristics of the inactive states, such as the ionic lock, the inward position of F6.44, and water clusters. Distinct conformational states are shown to be stabilized by each biased agonist. In particular, in simulations of the receptor with the ß-arrestin-biased agonist N-cyclopentylbutanepherine, we observe a different pattern of motions in helix 7 when compared to simulations with the G protein-biased agonist salbutamol that involves perturbations of the network of interactions within the NPxxY motif. Understanding the network of interactions induced by biased ligands and the subsequent receptor conformational shifts will lead to development of more efficient drugs.

Discrepant uptake of the radiolabeled norepinephrine analogues hydroxyephedrine (HED) and metaiodobenzylguanidine (MIBG) in rat hearts.

PURPOSE: (11)C-Hydroxyephedrine (HED) and radioiodinated metaiodobenzylguanidine ((123)I/(131)I-MIBG) are catecholamine analogue tracers for sympathetic nerve positron emission tomography/single photon emission computed tomography (PET/SPECT) imaging. In contrast to humans, rat hearts demonstrate high nonneural catecholamine uptake-2 in addition to neural uptake-1, the contributions of which to tracer accumulation are not fully elucidated. METHODS: Wistar rats were studied using the following pretreatments: uptake-1 blockade with desipramine 2 mg/kg IV, both uptake-1 and -2 blockade with phenoxybenzamine 50 mg/kg IV, or control with saline IV. HED or (123)I-MIBG was injected 10 min after pretreatment, and rats were sacrificed 10 min later. Heart to blood tissue count ratio (H/B ratio) was obtained using a gamma counter. To determine regional tracer uptake, dual-tracer autoradiography was performed with HED and (131)I-MIBG in Wistar rats with chronic infarction by transient coronary occlusion and reperfusion and in healthy control rats. Local tracer distributions were analyzed, and the infarcted rats' local tracer distributions were compared with histology. RESULTS: The H/B ratios in control hearts were 34.4 ± 1.7 and 25.5 ± 2.1 for HED and (123)I-MIBG, respectively. Desipramine led to a significant decrease in HED (3.2 ± 0.5, p < 0.0001), while there was no change in (123)I-MIBG (25.5 ± 6.4, p = n.s.). Phenoxybenzamine led to a significant decrease in both HED and (123)I-MIBG (3.5 ± 0.02, 4.3 ± 0.7, p < 0.0001). Only HED showed a subepicardium-subendocardium gradient in healthy control hearts which is consistent with physiological innervation, while (131)I-MIBG was evenly distributed throughout the myocardium. (131)I-MIBG uptake defect closely matched the scar area determined by histology [3.8 ± 2.3% ((131)I-MIBG defect) vs 4.0 ± 2.4% (scar)]. However, the scar area was clearly exceeded by the HED uptake defect (9.1 ± 2.2%, p < 0.001). CONCLUSION: HED uptake showed high specificity to neural uptake-1 in rat hearts. On the other hand, (123)I/(131)I-MIBG demonstrated distinct characters of regional tracer distribution and uptake mechanism that are compatible with significant contribution of nonneural uptake-2.

Preparation of polynorepinephrine adhesive coating via one-step self-polymerization for enantioselective capillary electrochromatography coupled with electrogenerated chemiluminesense detection.

For the first time, a simple and 'green' approach based on one-step strategy was designed and developed for the modification of a fused-silica capillary with polynorepinephrine (PNE) to separate amino acid enantiomers using capillary electrochromatography coupled with electrogenerated chemiluminescence detection (CEC-ECL). Norepinephrine (NE) was filled into capillary to generate PNE coating on the surface of capillary as permanent coating via the oxidation of NE by oxygen dissolvable in the solution. The formation of the PNE coating was characterized by scanning electron microscopy, UV-vis spectra and contact angle measurements. Compared with the native capillary, the modified capillary had much better wettability, less nonspecific adsorption toward amino acids, and the enantiomers of histidine, phenylalanine, and valine samples received baseline separation with the resolution factors of 1.6, 1.8 and 1.6, respectively, utilizing a separation length of 40 cm of the capillary coupled with ECL detection on the PNE-coated capillary.

[The pharmacological treatment of obesity: past, present and future]. / Az elhízás gyógyszeres kezelése: múlt, jelen, jövo

Currently, obesity presents one of the biggest health problems. Management strategies for weight reduction in obese individuals include changes in life style such as exercise and diet, behavioral therapy, and pharmacological treatment, and in certain cases surgical intervention. Diet and exercise are best for both prevention and treatment, but both require much discipline and are difficult to maintain. Drug treatment of obesity offer a possible adjunct, but it may only have modest results, limited by side effects; furthermore, the weight lowering effects last only as long as the drug is being taken and, unfortunately, as soon as the administration is stopped, the weight is regained. These strategies should be used in a combination for higher efficacy. Drugs used to induce weight loss have various effects: they increase satiety, reduce the absorption of nutrients or make metabolism faster; but their effect is usually moderate. In the past, several drugs were used in the pharmacological therapy of weight reduction including thyroid hormone, dinitrophenol, amphetamines and their analogues, e.g. fenfluramine, At present, only orlistat is available in the long term treatment (≥ 24 weeks) of obesity as sibutramine and rimonabant were withdrawn form the market. Several new anti-obesity drugs are being tested at present, and liraglutide, a GLP-1 analogue (incretin mimetic), is the most promising one.

Serotonergic and noradrenergic pathways are required for the anxiolytic-like and antidepressant-like behavioral effects of repeated vagal nerve stimulation in rats.

BACKGROUND: Vagal nerve stimulation (VNS) is used for treatment-refractory depression, but there are few preclinical studies of its effects when administered repeatedly over time using clinically relevant stimulation parameters in nonanesthetized animals. METHODS: The novelty-suppressed feeding test (NSFT) and forced swim test (FST) were used to evaluate the anxiolytic- and antidepressant-like potential of VNS in rats, respectively. The behavioral effects of VNS were compared with those of desipramine (DMI; 10 mg/kg/day) and sertraline (7.5 mg/kg/day) administered via osmotic minipump. Such experiments were carried out in intact rats as well as those that had selective destruction of either serotonin or noradrenergic neurons in brain caused by the neurotoxins, 5,7-dihyroxytryptamine (5,7-DHT), or 6-hydroxydopamine (6-OHDA). RESULTS: Repeated administration of VNS, DMI, and sertraline decreased latency to feed in the NSFT. In the FST, repeated VNS, DMI, and sertraline caused decreased immobility; the VNS-induced decrease in immobility resulted from increases in both swimming and climbing behaviors. Effects of VNS and sertraline, but not DMI, in both the NSFT and the FST were abolished in rats treated with 5,7-DHT. Effects of DMI in both behavioral tests, but not those of sertraline, were abolished in 6-OHDA treated rats. VNS effects on immobility and climbing in the FST were not blocked in the 6-OHDA-treated rats. There was no significant difference in locomotor activity caused by any of the treatments or by the lesions. CONCLUSIONS: Serotonergic nerves are required for repeated VNS-induced anxiolytic- and antidepressant-like effects. Noradrenergic nerves can also be activated by VNS to cause its anxiolytic-like effect.

Nocturnal hyperthermia induced by social stress in male tree shrews: relation to low testosterone and effects of age.

Stress is known to elevate core body temperature (CBT). We recorded CBT in a diurnal animal, the male tree shrew, during a one-week control period and a one-week period of social stress using a telemetric system. During the stress period, when animals were confronted with a dominant male for about 1h daily, CBT was increased throughout the day. We analyzed CBT during the night when animals were left undisturbed and displayed no locomotor activity. To determine whether nocturnal hyperthermia may be related to stress-induced changes in hormonal status, we measured testosterone, noradrenalin and cortisol in the animals' morning urine. The daily social stress increased the mean nocturnal temperature by 0.37 °C. Urinary testosterone was reduced during the stress period, and there was a significant negative correlation between testosterone and the area under the curve (AUC) of the nocturnal CBT. This means that stress-induced hyperthermia was strongest in the animals with the lowest testosterone concentrations. As expected, urinary noradrenalin was elevated during the stress week but a positive correlation with the AUC data was only found for animals younger than 12 months. Cortisol was also increased during the stress week but there were no correlations with nocturnal hyperthermia. However, the stress-induced increases in noradrenalin and cortisol correlated with each other. Furthermore, there were no correlations between the stress-induced increase in nocturnal CBT and body weight reduction or locomotor activity during the light phase. Interestingly, the extent of nocturnal hyperthermia depended on the animals' ages: In animals younger than 12 months, stress increased the AUC by 48%, in animals aged between 12 and 24 months, stress increased the AUC by 36%, and older animals showed only a 7% increase. However, testosterone was not significantly reduced in the older animals. The present data reveal an interrelation between the extent of stress-induced nocturnal hyperthermia, the animals' gonadal hormone status and their ages. The negative correlation between hyperthermia and testosterone indicates that this hormone in particular plays an important role in the regulation of body temperature in male tree shrews.