Antidepressant-Like Effects of ��-Opioid Receptor Antagonists in Wistar Kyoto Rats

The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased κ-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague–Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the number of c-fos-positive profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, respectively, in the WKY strain. In addition, local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants.     

Chemical Biology, Molecular Mechanism and Clinical Perspective of ��-Secretase Modulators in Alzheimer��s Disease

Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer''s disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.     

Immunosuppressive effects of intravenous self administration of dihydroetorphine on lymphocyte funct

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Immunostimulatory Effects of ��-glucan Purified from Paenibacillus polymyxa JB115 on Mouse Splenocytes

We investigated the effects of β-glucan purified from Paenibacillus polymyxa JB115 on the viability and proliferation of splenocytes. Splenocytes play a critical role in host immunity. MTT assays and trypan blue exclusion tests revealed that β-glucan significantly promoted the viability and proliferation of splenocytes over a range of concentrations. However, there was no specific subset change. β-glucan protected splenocytes from cytokine withdrawal-induced spontaneous cell death. For further mechanistic studies, ELISA assay revealed that β-glucan enhanced the expression of anti-apoptotic molecules and interleukin 7 (IL-7), a cytokine critical for lymphocyte survival. We also investigated the IL-2 dependency of β-glucan-treated splenocytes to determine if treated cells could still undergo clonal expansion. In flow cytometric analysis, β-glucan induced increased levels of the activation marker CD25 on the surface of splenocytes and β-glucan-treated splenocytes showed higher proliferation rates in response to IL-2 treatment. This study demonstrates that β-glucan can enhance the survival of splenocytes and provides valuable information to broaden the use of β-glucan in research fields.     

Bachelor��s Degree Programs in Clinical Pharmacy in China

This paper describes the status of the bachelor’s degree in clinical pharmacy education in China, with particular focus on educational institutions, programs, and curricula. The authors conducted a systematic literature review of clinical pharmacy education articles published from 2006 to 2011. To ensure the completeness of the investigation, an e-mail was sent or telephone call made directly to the colleges whose curriculum information could not be obtained by the above methodology. Twenty-three colleges offered a program in clinical pharmacy education in 2011. The colleges award either a bachelor of science or a bachelor of medicine degree with programs ranging from 4 to 5 years in duration. The 5-year BS degree program was most popular. Although the number of clinical pharmacy programs in China has steadily increased, more graduates and standardization of curricula are needed to meet the country’s steadily expanding need for quality health care.     

Opposite Effects of ��-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology

Δ-9-tetrahydrocannabinol (Δ-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Δ-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Δ-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Δ-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Δ-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Δ-9-THC. Δ-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Δ-9-tetrahydrocannabinol. Δ-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD''s ability to block the psychotogenic effects of Δ-9-THC.     

Cannabidiol Attenuates the Appetitive Effects of ��9-Tetrahydrocannabinol in Humans Smoking Their Chosen Cannabis

Worldwide cannabis dependence is increasing, as is the concentration of Δ₉-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.     

Clear cell ��sugar�� tumor of the lung �� case report

Background

The clear cell ??sugar?? tumor of the lung is an extremely rare benign mesenchymal tumor. Aim: To report a case of the sugar tumor and discuss diagnostic differentiation of the tumor.

Case report

A 53-year female presented with persisting cough. A CT scan revealed a round, 10 mm nodule located within the right lower lobe. The nodule was easily removed during thoracotomy. On the gross examination, the tumor was well circumscribed, and had a homogenous grayish-white appearance on the cut surface. The tumor consisted of round and oval cells with abundant clear cytoplasm, showing PAS pozitive abundant glycogen granules, which were removed by diastase pre-treatment before further staining with PAS. Immunohistochemical studies revealed the tumor cells were positive for HMB-45, vimentin, S-100 protein and very few cells for CD-117. The tumor cells were negative for ??SMA, CK-7, AE1/AE3, CD-10, chromogranin and TTF-1.

Conclusion

Based on the clinical, pathohistological and immunohistochemical data, the diagnosis of the primary clear cell sugar tumor of the lung was established.     

Instructional Scaffolding to Improve Students�� Skills in Evaluating Clinical Literature

Objective

To implement and assess the effectiveness of an activity to teach pharmacy students to critically evaluate clinical literature using instructional scaffolding and a Clinical Trial Evaluation Rubric.

Design

The literature evaluation activity centered on a single clinical research article and involved individual, small group, and large group instruction, with carefully structured, evidence-based scaffolds and support materials centered around 3 educational themes: (1) the reader''s awareness of text organization, (2) contextual/background information and vocabulary, and (3) questioning, prompting, and self-monitoring (metacognition).

Assessment

Students initially read the article, scored it using the rubric, and wrote an evaluation. Students then worked individually using a worksheet to identify and define 4 to 5 vocabulary/concept knowledge gaps. They then worked in small groups and as a class to further improve their skills. Finally, they assessed the same article using the rubric and writing a second evaluation. Students’ rubric scores for the article decreased significantly from a mean pre-activity score of 76.7% to a post-activity score of 61.7%, indicating that their skills in identifying weaknesses in the article''s study design had improved.

Conclusion

Use of instructional scaffolding in the form of vocabulary supports and the Clinical Trial Evaluation Rubric improved students’ ability to critically evaluate a clinical study compared to lecture-based coursework alone.     

The Necessity of ��4* Nicotinic Receptors in Nicotine-Driven Behaviors: Dissociation Between Reinforcing and Motor Effects of Nicotine

Here we utilize a mouse line with a targeted deletion of the α4 subunit (α4−/− mice), to investigate the role of α4^* nAChRs in reinforcing and locomotor effects of nicotine. Within a conditioned place preference paradigm, both α4−/− mice and wild-type (WT) littermates showed a similar place preference to nicotine (0.5 mg/kg i.p.) conditioning. When assessed for operant intravenous self-administration of nicotine (0.05 mg/kg/infusion), α4−/− mice did not differ from their WT littermates in self-administration behavior. To further examine a modulatory role for α4^* nAChRs in the reinforcing effects of nicotine, a transgenic mouse with a point mutation of the α4 subunit (α4-S248F) that renders increased sensitivity to low dose nicotine, was assessed for nicotine self-administration over a range of doses. At higher doses examined (0.05 and 0.07 mg/kg/infusion) there was no difference in intravenous nicotine self-administration; however, when mice were offered a lower dose of nicotine (0.03 mg/kg/infusion), α4-S248F mice showed greater nicotine intake than controls. Acute administration of 0.5 mg/kg nicotine caused significant locomotor depression in WT mice but α4−/− mice instead showed significant hyperactivity. Following chronic, intermittent administration of this dose of nicotine only WT mice displayed significant tolerance. Analogous experiments utilizing administration of the nicotinic antagonist mecamylamine in WT mice confirmed a dissociation between the putative nicotinic receptor subtypes required for mediating psychomotor and reinforcing effects of nicotine. These data demonstrate a necessary role for α4^* nAChRs in the locomotor depressant effect of nicotine but not the reinforcing effects that support ongoing self-administration of nicotine.     

The selectivity of ��-adrenoceptor agonists at human ��1-, ��2- and ��3-adrenoceptors

Background and purpose:

There are two important properties of receptor–ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor–ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 β-adrenoceptor agonists at the three human β-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy.

Experimental approach:

Stable clonal CHO-K1 cell lines, transfected with either the human β₁, β₂ or β₃-adrenoceptor, were used, and whole-cell [³H]-CGP 12177 radioligand binding and [³H]-cAMP accumulation were measured.

Key results:

Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the β₂-adrenoceptor over the β₁ or β₃), while others (e.g. isoprenaline) had little affinity–selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for β₁; clenbuterol, AZ 40140d, salbutamol for β₂) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the β₁- and β₃-adrenoceptors.

Conclusions and implications:

There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy.This article is commented on by Kenakin, pp. 1045–1047 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00764.x     

A Pharmacotherapy Capstone Course to Advance Pharmacy Students�� Clinical Documentation Skills

Objective. To implement and assess the effectiveness of a capstone pharmacotherapy course designed to integrate in-class curriculum using patient cases and drug-information questions. The course was intended to improve third-year doctor of pharmacy (PharmD) students'' clinical documentation skills in preparation for beginning advanced pharmacy practice experiences (APPEs). Design. This 2-credit, semester-long course consisted of 6 patient cases and 12 drug-information questions posted electronically on an Internet-based medical chart, a public health presentation, a knowledge examination, and an objective standardized performance assessment. In class, students engaged in active-learning exercises and clinical problem-solving. Students worked outside of class in small groups to retrieve and discuss assigned articles and review medication information in preparation for in-class discussions.Assessment. A rubric was used to assess the patient cases and questions that students completed and submitted individually. Data for 4 consecutive course offerings (n=622) were then analyzed. A significant improvement was found in the “misplaced” but not the “missing” documentation ratings for both assessment and plan notes in the final assessment compared with baseline. In course evaluations, the majority of students agreed that the course integrated material across the curriculum (97%) and improved their clinical writing skills (80.5%).Conclusion. A capstone pharmacy course was successful in integrating and reviewing much of the material covered across the PharmD curriculum and in improving students’ clinical documentation skills.     

Effects of schisanhenol on antitumoractivity of adriamycin

<正> It was suggested that adriamycin (ADM) may have at least two mechanisms of tissue damage. One, which involves lipid peroxidation, is blocked by the free radical scavenger, appears to play a major role in the development of cardiomyopathy. The other, which may involve binding of ADM to DNA, appears to be the major determinant of ADM toxicity for tumor cells. So the antitumor efficiency of ADM may be dissociated from its side effect of     

Effects of α2-receptors

Summary Clonidine has a dual action on naloxone-precipitated morphine withdrawal symptoms in rats: a suppressive action on body shakes and body weight loss and a potentiating action on jumping and aggression.It has been suggested that this potentiating, excitatory action is mediated by ₁-receptors. More specific ₂-agonists therefore should have a less excitatory effect on the latter symptoms. This hypothesis has been studied in rats dependent on morphine. Withdrawal was precipitated using naloxone. Prior to naloxone the ₂-agonists clonidine, guanfacine, azepexole, BHT-920, UK 14304 or the centrally acting ₁-agonist ST 587 were administered. All ₂-agonists but not the ₁-agonist potentiated the jumping and decreased body shakes and body weight loss.The effects of clonidine and azepexole were characterized pharmacologically using the -antagonists yohimbine and prazosin. Jumping potentiated by clonidine was antagonized by yohimbine whereas prazosin had no effect. Azepexole induced jumping was decreased by yohimbine both with respect to incidence and frequency, whereas prazosin only lowered the frequency. The suppressive actions of clonidine and azepexole on body shakes were reversed by yohimbine and not by prazosin. The data indicate that the potentiation of jumping by ₂-agonists as well as the suppression of body shakes in morphine withdrawal behaviour is mediated by ₂-receptors.     

Physicians�� perception of CPOE implementation

Objective To identify perceptions held by physicians of the benefits of computerized physician order entry (CPOE) and factors influencing its successful implementation in the context of the increased presence of a clinical pharmacist on ward. Setting A 2000-bed University Hospital. Method A cross-section opinion survey was conducted of all permanent physicians of the hospital to determine their perception on the benefits, or otherwise, of CPOE. Questionnaires, built upon the analysis of 10 preliminary semi-structured interviews with physicians, were sent to physicians by electronic and paper mail. It comprised three sections with a 4 level Likert scale: general perception of CPOE benefits (items 1.1?C1.8); opinion on the introduction of the CPOE system in the hospital (item 2); opinion on the presence of a pharmacist on ward (item 3). A fourth section recorded the respondent??s profile. Main outcome measures Level of agreement on the items describing the general perception of CPOE benefits; opinion on the introduction of a CPOE system in the hospital; and opinion on the pharmacist??s presence on ward. A Principal Component Analysis (PCA) was conducted on sections one and two. Analysis of this PCA representation in terms of the respondents?? profile was performed. Results One hundred and one physicians (18%) participated in the survey. Most (83%) physicians favoured the implementation of a CPOE (item 2). Among the advantages of CPOE, the greatest agreement concerned items related to safety and regulatory issues (from 80 to 76% agreement). Other items related to management issues were perceived as less tangible benefits (from 50 to 67% agreement). The increased presence of a pharmacist on the ward was supported by 94% of physicians. The PCA representation using profile items produced a 2-factor solution, accounting for 68% of the variance, with former experience of collaboration with a pharmacist (P = 0.002) and senior physician status (P = 0.013) positively influencing the perception of the CPOE. Conclusion Endorsement by senior physicians and the presence of a clinical pharmacist on ward promote a positive attitude towards CPOE and facilitate its implementation.     

Lateral Paracapsular GABAergic Synapses in the Basolateral Amygdala Contribute to the Anxiolytic Effects of ��3 Adrenoceptor Activation

Norepinephrine (NE) is known to play an integral role in the neurobiological response to stress. Exposure to stressful stimuli increases NE levels in brain regions that regulate stress and anxiety, like the basolateral amygdala (BLA). NE is thought to increase excitability in these areas through α- and β-adrenoceptors (ARs), leading to increased anxiety. Surprisingly, recent studies have shown that systemic β3-AR agonist administration decreases anxiety-like behaviors, suggesting that β3-ARs may inhibit excitability in anxiety-related brain regions. Therefore, in this study we integrated electrophysiological and behavioral approaches to test the hypothesis that the anxiolytic effects of β3-AR agonists may be mediated by an increase in BLA GABAergic inhibition. We examined the effect of a selective β3-AR agonist, BRL37344 (BRL), on GABAergic synapses arising from local circuit interneurons and inhibitory synapses originating from a recently described population of cells called lateral paracapsular (LPCS) interneurons. Surprisingly, BRL selectively enhanced LPCS-evoked inhibitory postsynaptic currents (eIPSCs) with no effect on local GABAergic inhibition. BRL also had no effect on glutamatergic synaptic excitation within the BLA. BRL potentiation of LPCS eIPSCs was blocked by the selective β3-AR antagonist, SR59230A, or by intracellular dialysis of Rp-CAMPS (cAMP-dependent protein kinase inhibitor), and this enhancement was not associated with any changes in spontaneous IPSCs or LPCS paired-pulse ratio. BRL also increased the amplitude of unitary LPCS IPSCs (uIPSCs) with no effect on uIPSC failure rate. Finally, bilateral BLA microinjection of BRL reduced anxiety-like behaviors in an open-field assay and the elevated plus-maze. Collectively, these data suggest that β3-AR activation selectively enhances LPCS, but not local, BLA GABAergic synapses, and that increases in LPCS-mediated inhibition may contribute to the anxiolytic profile of β3-AR agonists.