General practice pharmacists in England: Integration,mediation and professional dynamics

BackgroundA number of key publications in recent years have advocated a more integrated vision of UK primary care involving increased multi-professional communication and understanding. This has resulted in a marked change in the roles being undertaken by pharmacists. Community pharmacists have traditionally provided a medicine supply function and treated minor ailments in addition to delivering a suite of locally commissioned services; however these functions have not necessarily been part of a programme of care involving the other clinicians associated with the patient. An integrated model of care would see much closer working between pharmacy and general practice but also with pharmacists not only working with, but in the practice, in an enhanced patient-facing role, trained as independent prescribers. This has implications for the dynamics amongst professionals in this environment.ObjectivesThis exploratory multiple case study attempts to explore these changing dynamics across ten GP surgeries throughout the South-East of England.MethodsSemi-structured, in-depth interviews were conducted with one nurse, one pharmacist and one physician from each clinic, and survey data was collected from 38 patients who had appointments with a pharmacist.ResultsThe data suggested that the pharmacists who had enhanced roles perceived some uncertainty about their professional role and identity, which resulted in instability and insecurity and that this uncertainty led to both professional and interprofessional tension with their primary care colleagues. The survey data revealed that n = 35 (92%) patients stated they were ‘very satisfied’ or ‘satisfied’ with their appointment. And n = 37 (97%) were ‘very comfortable’ or ‘comfortable’ discussing their medications with the pharmacist. In addition, 36 patients (95%) reported that they strongly agreed or agreed with the clinical recommendations made by the pharmacist.ConclusionsThese findings are discussed in relation to role expansion and professional/interprofessional relations before key practical suggestions are offered.     

Interaction between Zinc,GPR39, BDNF and Neuropeptides in Depression

As one of the most important elements in our body, zinc plays a part in both the pathophysiology of depression and the antidepressant response. Patients suffering from major depression show significantly reduced zinc levels, which are normalized following successful antidepressant treatment. Recent studies have shown the interaction between zinc, GPR39 and neuropeptides, including galanin and neuropeptide Y (NPY). The zinc-sensing receptor GPR39 forms heterotrimers with 5-HT_1A and the galanin receptor GalR₁ upon their co-expression in mammalian cells. The oligomerization of these heterotrimers is regulated by the zinc concentration, and this may have an influence on depressive-like behavior. The antidepressant-like effect of zinc is linked to elevated levels of brain-derived neurotrophic factor (BDNF) in brain structures associated with emotion, such as the hippocampus and the amygdala. BDNF regulates neuropeptides, including NPY, cholecystokinin (CCK), and substance P or galanin, which are also implicated in mood disorders. This review focuses for the first time on the interaction between zinc, the GPR39 zinc receptor, BDNF and selected neuropeptides in terms of depression in order to determine its possible role in the neuropharmacology of that illness.     

莫西沙星、特非那定和卡托普利对犬生物遥测技术的评价研究

目的 用莫西沙星、特非那定和卡托普利对犬植入式生物遥测技术进行性能评价研究。方法 4只埋植有遥测植入子的清醒Beagle犬,通过拉丁方设计,在4个不同的给药日分别ig给予空白胶囊、莫西沙星、特非那定和卡托普利30 mg/kg,用DSI遥测系统连续采集给药前2 h至给药后24 h的生理信号,对心电、血压、体温等数据进行分析,比较给药前与给药后各时间点各指标的差异。结果 空白胶囊对犬的各项生理指标无明显影响;给予莫西沙星和特非那定后,犬QT间期及校正的QT间期（QTc）与给药前比较,出现不同程度的延长;给予卡托普利对犬的心电参数无影响但显著降低血压。结论 植入式生物遥测技术可灵敏的检测到药物对清醒犬心血管系统的影响,可用于安全药理研究和清醒犬心血管模型研究。     

KP544, a nerve growth factor amplifier: Pharmacokinetics,safety, and efficacy in the rat

In cultured cells, KP544 [2‐amino‐5‐(4‐chlorophenylethynyl)‐4‐(4‐trans‐hydroxycyclohexyl amino) pyrimidine] amplifies differentiation initiated by nerve growth factor (NGF) or cAMP. This report describes the pharmacokinetics, safety, and neuroprotective efficacy of KP544 in rats. After an oral dose of 10 mg/kg KP544 was 25% bioavailable with a plasma half‐life of 1.3 h and brain levels 6‐fold higher than plasma levels at 4 and 8 h post‐dose. In a safety study, daily oral dosing for 30 days at 10 and 100 mg/kg was well tolerated. The favorable pharmacokinetic and safety profiles, together with its amplification of NGF in vitro, prompted evaluation of KP544 in two models involving NGF deficiencies. In the first model, brains were lesioned with intrastriatal injections of quinolinic acid. KP544 at oral doses of 0.02 to 1.0 mg/kg/day almost completely prevented the resulting learning deficits as evaluated using a radial‐arm‐water maze. At the lowest dose, there was a slower onset of functional improvement. These effects were accompanied by reductions (16–34%) in the striatal lesion size that were greatest at the highest dose and comparable to those seen with NGF therapy. The second model involved a peripheral neuropathy induced by taxol that is associated with decreases in NGF. KP544 at oral doses of 0.1–10 mg/kg/day decreased the severity of the neuropathy as measured by caudal nerve conduction velocities (30–70% return to control values). In both models, KP544 had a large therapeutic index suggesting its potential as a new approach for treating clinical disorders involving deficiencies in NGF. Drug Dev. Res. 62:60–70, 2004. © 2004 Wiley‐Liss, Inc.     

HPLC法测定醒脾养儿颗粒中熊果苷、槲皮苷、缬草三酯和乙酰缬草三酯

目的建立HPLC波长切换法同时测定醒脾养儿颗粒中的熊果苷、槲皮苷、缬草三酯和乙酰缬草三酯。方法采用HPLC法,Agilent HC-C_(18)柱色谱柱(250 mm×4.6 mm,5μm);流动相:乙腈–0.4%磷酸溶液,梯度洗脱;0~14 min时在280 nm波长下检测熊果苷,14~18 min在350 nm波长下检测槲皮苷,18~30 min在256 nm波长下检测缬草三酯和乙酰缬草三酯;体积流量:0.9 m L/min;柱温:25℃;进样量为10μL。结果熊果苷、槲皮苷、缬草三酯和乙酰缬草三酯分别在11.97~239.40μg/m L、4.65~93.00μg/m L、4.18~83.60μg/m L、5.30~106.00μg/m L峰面积与质量浓度呈良好的线性关系,r分别为0.999 8、0.999 3、0.999 9、0.999 5;平均回收率分别为98.78%、97.11%、99.14%、98.75%,RSD值分别为1.62%、0.68%、1.39%、0.87%。结论所建立的方法样品处理方法简便,检测的准确性和重复性均较好,可为醒脾养儿颗粒质量标准测定方法的制定提供依据。     

Inhibition of adenosine uptake in human erythrocytes by adenosine-5'-carboxamides,xylosyladenine, dipyridamole,hexobendine, and p-nitrobenzylthioguanosine

Adenosine uptake in human erythrocytes at 0° consists of a saturable and a concentration-proportional component, the latter seems to represent uptake into a pericellulai compartment inaccessible to inulin. Xylosyladenine and derivatives of adenosine-5'-carboxamide were found to be weak inhibitors of the saturable component of adenosine uptake with apparent K_i values at least one order of magnitude higher than the apparent K_m for adenosine (2.4 × 10^?6 M). The affinity of the adenine nucleosides to the saturable uptake process appears to depend not only on the 3'-hydroxy] group and its erythro-configuration but also on the 5'-substituent. Dipyridamole, hexobendine, and p-nitrobenzylthioguanosine, by contrast, had K_i values at least one order of magnitude lower than the K_m for adenosine. The steric requirements for binding of the adenine furanosides to the putative smooth muscle receptors mediating vasodilation. on the the one hand, and to the saturable cellular uptake mechanism, on the other hand, were found to be different.     

Autophagy,mitochondria and 3-nitropropionic acid joined in the same model

Huntington''s disease (HD) is a neurodegenerative disorder caused by a mutation in the gene encoding the huntingtin protein. Although the precise mechanism by which neuronal degeneration occurs is still unclear, several elements are important to its development: (1) altered gene expression and protein synthesis, (2) mitochondrial damage and (3) improper regulation of the autophagy programme. In this issue of British Journal of Pharmacology, Galindo and co-workers provide the first evidence for a role of the mitochondrial permeability transition pore (mPTP) in mitochondrial fragmentation and autophagy activation. In a model of cell death induced by 3-nitropropionic acid (3-NP) in human neural cells, the authors describe clear functions for mPTP and Bax, but not the mitochondrial fusion/fission machinery, mitochondrial fragmentation and autophagy (mitophagy). This commentary summarises the significance of this relationship and suggests several points for future development.     

克罗恩病患者疾病活动指数应对方式与抑郁的相关性研究

目的 调查分析克罗恩病患者的疾病活动指数、应对方式与抑郁的相关性,为制订针对性的干预措施提供依据。 方法 以Harvey简化CDAI计算法、抑郁自评量表(SDS) 、应对方式量表(MCMQ)对100例克罗恩病患者进行调查。 结果 62%的克罗恩病患者存在抑郁;克罗恩病患者疾病活动指数与抑郁呈正相关(r=0.556,P< 0.01);面对与抑郁呈负相关(r=-0.578,P< 0.01);回避与抑郁呈正相关(r=0.165,P< 0.05);屈服与抑郁呈正相关(r=0.215,P< 0.01)。 结论 克罗恩病患者多存在抑郁,与疾病程度和应对方式有一定相关性,护理人员应根据患者特点进行心理护理,减少患者抑郁。     

基于网络药理学、分子对接及分子动力学模拟探讨甘草查尔酮A治疗阿尔茨海默病的作用机制研究

目的 从分子层面探讨甘草查尔酮A治疗阿尔茨海默病（AD）的作用机制。方法 通过TCMSP、PharmMapper、SwissTargetPrediction、CTD及DisGeNET等数据库检索出甘草查尔酮A的作用靶点及其与AD相关的靶点的交集。利用Cytoscape 3.7.2软件的ClueGO功能对交集蛋白作KEGG通路富集分析。最终通过分子对接及分子动力学模拟方法从分子层面研究甘草查尔酮A作用于AD相关靶点的结合位点及结合能力。结果 甘草查尔酮A的作用靶点有128个,其中与AD相关的靶点112个,这些靶点涉及信号通路33条,包括MicroRNAs in cancer、Serotonergic synapse及Cell cycle等,从而构建出靶蛋白蛋白相互作用（PPI）、单一成分-靶点-生物学通路网络。分子对接及分子动力学模拟结果显示,甘草查尔酮A与PPI网络图中度值最高的20个靶蛋白均能很好地结合,其中结合性最好的3个靶蛋白分别为视网膜母细胞瘤相关蛋白、环氧合酶2和丁酰胆碱酯酶。结论 从分子层面对甘草查尔酮A治疗AD作用机制进行初步探讨,揭示潜在的生物学机制,为其应用提供理论依据。     

Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor

BACKGROUND AND PURPOSE

Graves'' disease (GD) is an autoimmune disease in which the thyroid is overactive, producing excessive amounts of thyroid hormones, caused by thyroid-stimulating hormone (TSH) receptor-stimulating immunoglobulins (TSIs). Many GD patients also suffer from thyroid eye disease (Graves'' ophthalmopathy or GO), as TSIs also activate TSH receptors in orbital tissue. We recently developed low molecular weight (LMW) TSH receptor antagonists as a novel therapeutic strategy for the treatment of GD and GO. Here, we determined the molecular pharmacology of a prototypic, nanomolar potent LMW TSH receptor antagonist, Org 274179-0.

EXPERIMENTAL APPROACH

Using CHO cells heterogeneously expressing human TSH receptors and rat FRTL-5 cells endogenously expressing rat TSH receptors, we determined the potency and efficacy of Org 274179-0 at antagonizing TSH- and TSI-induced TSH receptor signalling and its cross-reactivity at related follicle-stimulating hormone and luteinizing hormone receptors. We analysed the allosteric mode of interaction of Org 274179-0 and determined whether it is an inverse agonist at five naturally occurring, constitutively active TSH receptor mutants.

KEY RESULTS

Nanomolar concentrations of Org 274179-0 completely inhibited TSH (and TSI)-mediated TSH receptor activation with little effect on the potency of TSH, in accordance with an allosteric mechanism of action. Conversely, increasing levels of TSH receptor stimulation only marginally reduced the antagonist potency of Org 274179-0. Org 274179-0 fully blocked the increased basal activity of all the constitutively active TSH receptor mutants tested with nanomolar potencies.

CONCLUSIONS AND IMPLICATIONS

Nanomolar potent TSH receptor antagonists like Org 274179-0 have therapeutic potential for the treatment of GD and GO.     

创新赋能儿童药物研究，技术引领儿科药学发展

儿童用药问题一直是公众关注的热点。鼓励儿童药物研究创新，推进儿童用药多领域、多学科融合发展任重而道远。为持续推动儿童药物创新，合力攻关儿童用药难题，保障儿童用药可及性及安全性，本期推出“儿童药物研究”专刊，分别从“儿童用药问题与对策”“儿童药物研究前沿技术”“儿童药物临床研究”“儿童药物监测”“儿童药物警戒”五大主题深入探讨，将为广大儿童药物研究同道提供临床借鉴、研究基础和思路拓展，进一步促进儿童合理用药和儿童药物研发的蓬勃发展。     

Engagement in Alcohol Treatment: The Client's Experience of,and Satisfaction with,the Assessment Interview

Clients' experiences of routine alcohol assessment interviews at a therapeutic day unit were studied in order to enhance understanding of the factors associated with subsequent engagement in treatment. The paper describes the development and use of the Client's Experiences and Satisfaction Questionnaire. The main finding from its use with 131 clients, was a positive association between the client's perceptions of the quality of the therapeutic relationship established during the interview, and subsequent engagement in treatment. Large differences were found between the engagement rates of different workers. Clients who were being referred for the first time and those with a SADQ score below 30 were less likely to engage. The findings are augmented with quotes from the clients themselves.     

Stimulatory effect of ionophores on adenosine 3',5'-monophosphate content in human mononuclear leukocytes

Ionophores A23187 and bromo-lasalocid ethanolate enhanced the cyclic AMP content in human mononuclear leukocytes. The maximum effect of A23187 with a 10-min incubation was found with 0.3–1.0μM concentrations with or without l-isoproterenol (1 μM) or prostaglandin E ₁ (pge ₁) (0.3 μM). The maximum effect after 5 min of incubation at 37° was observed with 0.05, 0.2 and 1 μm A23187. The effect of ionophore A23187 was enhanced by both aminophylline (1 mM) and isobutyl-methylxanthine (1 mM). Calcium (1 mM). aspirin (1 mM) and indomethacin (100 μM) decreased the stimulatory action of A23187. Bromo-lasalocid ethanolate increased cyclic AMP content in cells maximally at a 3 μM concentration with or without 0.3 μM pge ₁.     

Mitochondrial Biology and Neurological Diseases

Mitochondria are extremely active organelles that perform a variety of roles in the cell including energy production, regulation of calcium homeostasis, apoptosis, and population maintenance through fission and fusion. Mitochondrial dysfunction in the form of oxidative stress and mutations can contribute to the pathogenesis of various neurodegenerative diseases such as Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s diseases (HD). Abnormalities of Complex I function in the electron transport chain have been implicated in some neurodegenerative diseases, inhibiting ATP production and generating reactive oxygen species that can cause major damage to mitochondriaMutations in both nuclear and mitochondrial DNA can contribute to neurodegenerative disease, although the pathogenesis of these conditions tends to focus on nuclear mutations. In PD, nuclear genome mutations in the PINK1 and parkin genes have been implicated in neurodegeneration [1], while mutations in APP, PSEN1 and PSEN2 have been implicated in a variety of clinical symptoms of AD [5]. Mutant htt protein is known to cause HD [2]. Much progress has been made to determine some causes of these neurodegenerative diseases, though permanent treatments have yet to be developed. In this review, we discuss the roles of mitochondrial dysfunction in the pathogenesis of these diseases.     

Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage

BACKGROUND AND PURPOSE

Prevention or disease-modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimer''s disease, Parkinson''s disease and Huntington''s disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson''s disease models.

EXPERIMENTAL APPROACH

Mesencephalic neuron–glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured toxicity in dopaminergic neurons, using dopamine uptake assay and morphological analysis and expression of neurotrophic substances by enzyme-linked immunosorbent assay and real-time RT PCR.

KEY RESULTS

In mesencephalic neuron–glia cultures, SAHA displayed dose- and time-dependent prolongation of the survival and protection against neurotoxin-induced neuronal death of dopaminergic neurons. Mechanistic studies revealed that the neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation.

CONCLUSION AND IMPLICATIONS

The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases.