Editorial

A themed section in this issue of Br J Pharmacol, on ‘Advances in Nutritional Pharmacology’, provides a valuable and timely update on progress in this area.The value of dietary components to improvement in health and, particularly, to prevention of cardiovascular disease and cancer, is frequently reported in the media and therefore often captures the attention of the wider public. Understanding the pharmacological mechanisms by which nutritional elements confer their health benefits enables us to keep the public informed, but also aids in the identification of new targets for drug development. In recent years there has been significant progress in this field.Four rapidly developing areas are reviewed. Vosper (2009) covers the identification of a receptor for niacin and the subsequent development of selective agonists as lipid lowering agents. Wu-Wong (2009) describes the development of new Vitamin D analogues for the treatment of cardiovascular disease. de Roos et al. (2009) provide detailed insight into how omega-3 fatty acids, also known as longchain n-3 polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease. Zhou et al. (2009) cover the mechanisms underlying the beneficial effects of resveretrol in protection against cancer.These reviews are complimented by three key original articles focusing on endogenous mechanisms of weight control involving endocannabinoids (Izzo et al., 2009), a circulating protein, the soluble leptin receptor (Zhang & Scarpace, 2009) and a treatment, zinc plus cyclo-(His-Pro) (CHP), known to increase insulin metabolism (Song et al., 2009).The value of dietary components to improvement in health and, particularly, to prevention of cardiovascular disease and cancer, is frequently reported in the media and therefore often captures the attention of the wider public. Understanding the pharmacological mechanisms by which nutritional elements confer their health benefits enables us to keep the public informed, but also aids in the identification of new targets for drug development. In recent years there has been significant progress in this field.A themed section in this issue of Br J Pharmacol, on ‘Advances in Nutritional Pharmacology’, edited by Cherry Wainwright, aims to provide a valuable and timely update on progress in this area.This issue includes several reviews that provide an update in four rapidly developing areas. Vosper (2009) has written a narrative tracking the research that led to the identification of a receptor for niacin and the subsequent development of selective agonists as lipid lowering agents. Within this review, the benefits and pitfalls of niacin receptor agonists are discussed, alongside a consideration of the impact of blocking their undesirable effects, such as skin flushing. Two further reviews describe the development of new Vitamin D analogues for the treatment of cardiovascular disease(Wu-Wong, 2009) and provide detailed insight into how omega-3 fatty acids, also known as longchain n-3 polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease (de Roos et al., 2009). The fourth review provides greater understanding of the mechanisms underlying the beneficial effects of resveretrol in protection against cancer (Zhou, 2009).These reviews are complimented by three key original articles focusing on endogenous mechanisms of weight control. In an elegant study in lean and fatty mice with diet induced obesity, Izzo et al. (2009) have provided evidence to support the idea that dysregulation of peripheral endocannabinoids can contribute to obesity. In a further in vivo study, direct evidence is provided that a circulating protein, the soluble leptin receptor, may play a regulatory role in energy homeostasis and weight gain by neutralizing leptin (Zhang & Scarpace, 2009). Finally Song et al. (2009) have demonstrated in both diabetic and non-diabetic overweight aged rats that zinc plus cyclo-(His-Pro) (CHP), a treatment known to increase insulin metabolism, improves weight control through reducing food intake and altering the balance between plasma leptin and adiponectin levels, suggesting this may be a possible treatment for overweight and obese patients.     

Editorial

Cell movement is a fundamental process of normal cellular physiology and pathophysiology. Abnormal regulation of cell migration is a common denominator of many medical disorders, including cancer metastasis, autoimmune disease and inflammation. Increased interest in the targeting of cell migration and invasion, which has potential for therapeutic intervention in many diseases are behind this special themed issue. Thus, the focus of this issue is centred on the control of cellular cytoskeletal dynamics and cellular or tissue microenvironment sensors. Novel therapeutic opportunities targeting regulation of cell migration are discussed including the emerging roles of tetraspanins, phosphoinositides, transient receptor potential cation channels, stromal interaction molecules and calcium release-activated calcium modulators. Better understanding of these regulatory factors will hopefully bring greater attention to strategically targeting aberrant cell migration, which has many therapeutic implications for common human diseases.

Linked Articles

This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24The regulation of cell migration is complex and involves sequential chains of events in both normal and pathological conditions. This complexity has proven to be a challenge in therapeutic development but at the same time offers interventional opportunities. Cytoskeletal dynamics involves various regulatory processes, which offers several potential intervention points for anti-migration drugs. In this issue, leading scientists in the area of inflammation, wound healing and tumour biology have contributed an overview of cell migration and perspectives on the clinical application of anti-migration therapeutics. There is discussion of new and/or emerging roles of novel therapeutic interventions targeting cytoskeletal dynamics such as membrane lipids, the Ras superfamily of small GTPase proteins, transmembrane spanning tetraspanins, calcium sensors and ion channels.In cancer, cell migration is required for local invasion, angiogenesis and metastasis, which are common characteristics for all cancers, as reviewed by Hanahan and Weinberg 2011. Cancer morbidity and mortality are largely related to the spread of the primary, localized tumour to adjacent and distant sites. Appropriate management and treatment decisions for metastatic disease are crucial and are better informed by greater understanding of the metastatic process. There are common events that occur during metastasis: dissociation from the primary tumour mass, reorganization/remodelling of extracellular matrix, cell migration, recognition and traversal of endothelial cells into the vascular circulation and lodgement and proliferation within ectopic stroma. One of the key and initial events is the increased capability of cancer cells to move through tissue planes and escaping normal physiological constraints. The first of the anti-migration class of inhibitors to be approved for multiple sclerosis and Crohn''s disease is natalizumab (Selewski et al., 2010); the migration-inhibitory mode of action of natalizumab is through its antibody-tail binding to α4 integrin on lymphocytes preventing its binding to endothelial cells, hence transmigration across vascular endothelium (Yednock et al., 1992; Tubridy et al., 1999). Detchokul et al. (2014) have also reviewed the emerging role of members of the transmembrane-4-superfamily (or tetraspanins) in the regulation of cancer migratory processes and the potential of therapeutic targets against tetraspanins and their binding partners, including integrins, matrix metalloproteinases, EWI proteins (a cell surface immunoglobulin SF protein) and E-cadherin.The cellular cytoskeleton is at the heart of the cell migration process in both normal and pathological conditions (Fletcher and Mullins, 2014; Stricker et al., 2010; Rottner and Stradal, 2011; Ratheesh and Yap, 2012). An active change in cancer cytoskeletal dynamics results in manipulation of plasma membrane and cellular balance between cellular adhesion and motility which in turn determines cancer cell movement. In this issue, Fife et al. (2014) discuss the role of the cytoskeletal proteins, namely actins, intermediate filaments and microtubules, in cancer migration and metastasis. In particular, the role of microtubules in the regulation of migration, invasion and metastasis in various cancers was highlighted. Increasing evidence reveal that microtubule and actin cytoskeletal dynamics are both controlled by Rho family of GTPases (Rho-GTPases). Microtubules, in turn, are able to mediate Rho-GTPases. Crosstalk between actin and microtubules does occur, which furthermore underscores the regulatory role of microtubule systems to the actin cytoskeletal regulation. This new knowledge opens doors to discovery of new biomarkers and therapeutic targets for cancer migration and metastasis. Biro et al. (2014) have also given a comprehensive review on the regulatory pathways of actomyosin dynamics in immune cell migration. They draw attention to the therapeutic intervention points from the downstream signalling in Rho-GTPase pathways such as Rho kinase (ROCK), Cdc42 and Rac. Increasing understanding of the control of these molecules has led to the development of pharmaceutical compounds acting against these molecules.Another regulatory mechanism of the actin cytoskeleton dynamics is via actin binding proteins and membrane lipids, as reviewed by Wu et al. (2014). The PI3K signalling pathway (i.e. PI3K–AKT–mTOR) is well-recognized as dysregulated in many cancers, including breast cancer, multiple myeloma, leukaemia, lymphoma (Samuels and Waldman, 2010; Jensen et al., 2012) and inflammatory respiratory diseases (Ito et al., 2007; Doukas et al., 2009). Many candidate inhibitors have been developed to counteract members of this pathway (Liu et al., 2009; Cheng et al., 2014; Marcias-Perez and Flinn, 2013; Yang et al., 2013). Nevertheless, most single-agent cancer trials did not yield anticipated results (Fruman and Rommel, 2014), leading to further searches for more specific targeting such as different isoforms of PI3K (Ameriks and Venable, 2009). Chen et al., in this issue, has reviewed the current understanding of metabolism of phosphoinositides in particular PI(4,5)P₂ and PI(3,4,5)P_2, and discussed their multiple involvements in the regulation of actin binding proteins. These multidimensional roles of phosphoinositides may be indicative of challenging outcomes for targeting the PI3K signalling pathway, as seen in early phase clinical trials.Earlier this year, the BJP published a very informative themed issue on transient receptor potential (TRP) channel superfamily (Holzer and Izzo, 2014) bringing forth their importance in many pathological conditions, namely pain sensation, bladder dysfunction and pulmonary diseases. In the current issue, Nielsen et al. (2014) comprehensively review the role of TRP channels and functional partners Ca²⁺ sensitive stromal interaction molecule (STIM)/calcium release-activated calcium modulator (ORAI) proteins in cancer migration and metastasis. Increasing evidence has been found of the role stromal cells play in cancer metastasis; TRP channels and STIM/ORAI proteins have a potential role in the regulation of crosstalk between cancer and stromal cells and thereby influence the migration of both cell types. Besides being cellular environmental sensors, TRP channels are linked to the actomyosin cytoskeleton. This review summarizes their role as sensors and effectors in cancer migration and metastasis and detailed subtype expression in various cancers was also summarized, supporting a potential role of these proteins as drug targets.Taken together, these reviews represent for the reader a sample of active research in the cell migration field, the hope being that greater mechanistic understanding might now lead to novel therapeutic approaches to common conditions such as cancer and inflammatory disorders.     

Arylamine N-acetyltransferases: a structural perspective. Comments regarding the BJP paper by Zhou et al., 2013

This letter is a comment on Zhou et al. (2013). Arylamine N-acetyltransferases: a structural perspective. Br J Pharmacol 169: 748–760. To view this article visit http://dx.doi.org/10.1111/bph.12182We have read with great interest the recent review published by the British Journal of Pharmacology entitled ‘Arylamine N-acetyltransferases: A structural perspective’ (Zhou et al., 2013). This review highlights, from a structural point of view, the importance of the arylamine N-acetyltransferases (NAT) family of xenobiotic-metabolizing enzymes in the biotransformation of aromatic amine drugs and carcinogens and describes emerging new functions these enzymes may possess. The determination of the three-dimensional structure of prokaryotic and eukaryotic NAT enzymes has led to many advances in the understanding of their catalytic mechanisms, substrate specificity and the effect of polymorphisms on their function. In addition, the elucidation of these crystal structures has also contributed to the development of specific inhibitors of certain NAT isoforms (Sim et al., 2012). Although the review by Zhou et al., (2013) is topical and of great interest, several important elements described below would complete the overview of NAT structure and function.As of 5 April 2013, the Protein Databank (PDB) contains 15 crystal structures of NAT enzymes (from eight prokaryotic NATs and two human NATs). This number of crystal structures has not changed since February 2012. In particular, Zhou et al., (2013) overlooked three crystal structures that were published in the last 5 years: Nocardia farcinica NAT [PDB 3D9W, (Martins et al., 2008)], Mycobacterium marinum NAT in complex with hydralazine drug [PDB 3LTW, (Abuhammad et al., 2010)] and Bacillus anthracis NAT1 in complex with coenzyme A [PDB 3LNB, (Pluvinage et al., 2011)]. In addition, the structure of an NAT isoform from Bacillus cereus has been deposited in the PDB (4DMO) and its coordinates will be available in May 2013; the crystallization of this NAT enzyme was published early last year (Kubiak et al., 2012).The structure of M. marinum NAT complexed with hydralazine sheds light on the binding of this drug to an NAT enzyme and reveals a novel mechanism for the acetylation reaction that results in the production of a 3-methyltriazolo[3,4-a]phthalazine ring compound (Abuhammad et al., 2010). In addition, the structure of NAT1 from B. anthracis in complex with coenzyme A (CoA) demonstrates that the 17-residue insertion previously described as specific to human NAT enzymes (and, more broadly, to mammalian NAT isozymes) is also present in certain prokaryotic NAT enzymes (Pluvinage et al., 2011). This structure also reveals a new mode of binding of the cofactor CoA when compared with the crystal structures of M. marinum NAT and human NAT2 (Pluvinage et al., 2011). Thus, the mode of binding of acetylCoA is more diverse than originally thought and varies among NAT enzymes.Another point pertinent to the review deals with the models for the chemical reaction that occurs at the NAT active site. The authors do describe the important work done by Wagner/Hanna''s group on the hamster NAT2 enzyme showing, in particular, the existence of a thiolate-imidazolium pair at the active site (Wang et al., 2004; 2005). However, the work done by Blanchard and colleagues on a prokaryotic NAT enzyme (the NAT from Mycobacterium tuberculosis), which identified a completely different mechanism from that observed with the hamster NAT2 (Sikora et al., 2008), also deserves attention. In essence, Sikora et al. found that the enzyme has a catalytic cysteine pKa higher than 10, suggesting that the catalytic residue must be protonated at physiological pH and in the presence of substrate before nucleophile attack on acetylCoA occurs. Furthermore, these data do not corroborate the existence of a thiolate/imidazolium ion pair at physiological pH but, rather, indicate a general base catalysis for the M. tuberculosis NAT enzyme. This finding suggests that the catalytic mechanism of NAT enzymes from different organisms can also vary.This letter should not be viewed as a negative commentary on the article of Zhou et al., who have provided a clear and straightforward review of the exciting novel aspects of the NAT field. On the contrary, we hope our letter complements their review and provides further information on these important aspects of NAT structure and function.     

Ecstasy cannot be assumed to be 3,4-methylenedioxyamphetamine (MDMA)

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This is a rebuttal by the authors (Green et al., pp. 1523–1536 of this issue) to a commentary by Parrott, pp. 1518–1520 of this issue. To view the article by Green et al. visit http://dx.doi.org/10.1111/j.1476-5381.2011.01819.x. To view the commentary by Parrott visit http://dx.doi.org/10.1111/j.1476-5381.2012.01941.xWe thank Prof Parrott (Parrott 2012) for his interest in our review (Green et al., 2012). Our main aim was to discuss the problems that arise in interpreting data obtained when administering 3,4-methylenedioxymethamphetamine (MDMA) to experimental animals in terms of possible clinical consequences and vice versa, not to disparage the evidence that Ecstasy is neurotoxic in humans. We presented evidence that the pharmacokinetics of MDMA in rats and primates are fundamentally different from the pharmacokinetics of the drug in humans. Because the plasma half-life of the drug in rats is 10 times shorter than in humans, the acute adverse events in rats may be minimal compared with those in humans, and this includes body temperature and endocrine changes. Conversely, the rapid metabolism of the drug in rats to form neurotoxic metabolites may result in more severe long-term effects in that species than those that may occur in humans.We had no intention of suggesting that there was no evidence for some recreational Ecstasy users presenting with evidence of 5-HT neurotoxicity, albeit it is clear from the literature that some of this evidence remains open to several interpretations. What we did claim was that pure 3,4-methylenedioxymethamphetamine (MDMA) taken alone was unlikely to cause 5-HT neurotoxicity in man. Here we must emphasize the term MDMA, as it is crucial to our discussion. Parrott, in contrast, uses the term ‘Ecstasy/MDMA’ several times when discussing neurotoxicity (Parrott, 2012). This association of Ecstasy with MDMA is one of the major problems of translation that we addressed. The Ecstasy tablet that most recreational users buy and ingest is not necessarily MDMA. Indeed, in many cases, it clearly is not. The tablet is often adulterated with other compounds, and one investigation identified no less than 14 substances other than MDMA in Ecstasy tablets, which users nevertheless presumably believed contained only MDMA (Vogels et al., 2009). Many of the adulterants identified were also psychoactive and included compounds structurally related to MDMA such as 3,4-methylenedioxyethylamphetamine and 2-methylamino-1-(3,4-methylenedioxyphenyl)butane, which have poorly researched pharmacology and toxicology. In addition, most recreational users of Ecstasy also knowingly ingest other psychoactive compounds such as alcohol and cannabis. Alcohol, for example, alters the pharmacokinetics of MDMA (Hamida et al., 2009). While, as Parrott states, clinical studies have attempted to allow for these confounding factors in any examination of the physical and psychological effects of MDMA in humans, such analysis is always limited not only by the other compounds the evaluators are unaware of, but also drugs perhaps not even considered to be relevant by the user and therefore not disclosed. It is unlikely that coffee and ‘energy drinks’ such as Red Bull are always disclosed, but there is now good preclinical evidence that caffeine, which incidentally has also been found as an adulterant in Ecstasy tablets, enhances both the hyperthermia and neurotoxicity induced in rats by MDMA (Camarasa et al., 2006; Vanattou-Saïfoudine et al., 2010). And this brings us to the crux of the problem and weakness of all the clinical data cited by Parrott (2012). A basic tenet of all good clinical pharmacology is accurate knowledge of the doses administered, frequency of administration and any confounding factors such as other drugs being consumed. None of these data are available with any precision in the clinical studies quoted. Of course one has some indication as to dose (although as Vogels et al., (2009) reported, the dose contained in illicitly obtained tablets is highly variable) and frequency of drug ingestion, but this information is generally obtained from the user whose recall is likely to be limited or who decides to obfuscate. Crucially, the information can never take into account the problem of drug tablet adulteration. The fact that hair or urine samples detect MDMA merely shows the user has consumed the drug, not how much or when or what other drugs were taken concurrently.We never suggested that MDMA exposure was not going to be associated with physical or psychological change. However such changes are not necessarily associated with long-term neurotoxic damage. We have shown that long-term behavioural effects can occur in rats both with and without 5-HT neurotoxicity (Fone et al., 2002; Bull et al., 2003; Rodsiri et al., 2011). It is interesting that Parrott approvingly quotes the Verheyden et al. (2003) study in support of his contention that neurotoxic damage has occurred. Because this study noted that the majority of persons reporting chronic psychiatric problems reported ‘improved mental health’ after quitting the drug, this surely allows us to conclude that the drug had produced subacute changes rather than any that could be associated with long-term neurotoxic damage.A further limitation to any clinical study is that one cannot perform prospective studies with the aim of investigating whether long-term neurotoxic events occur, so weaknesses arise with regard to any psychological abnormalities observed. Are persons with high risk of psychiatric problems more likely to misuse the drug, or does the drug induce changes in high-risk individuals? If high risk also happened to be associated with 5-HT abnormalities in the brains, then any conclusion that MDMA has induced neurotoxicity is spurious.We most certainly did not suggest that MDMA acted as a neurotoxin only under conditions of severe hyperthermia as is stated by Parrot in his sixth paragraph (Parrott, 2012). We have been involved in many studies on the effects of MDMA on body temperature in rats (see Docherty and Green, 2010) including one that demonstrated that neurotoxicity can occur in the absence of hyperthermia (O''Shea et al., 1998) and another that showed that hyperthermia worsens neurotoxic damage (Green et al., 2004). In our review, what we did propose was that because of the very different pharmacokinetics of MDMA in rats and humans, it is probable that humans would suffer serious or fatal adverse events at plasma levels below those likely to be required to induce 5-HT neurotoxicity.We emphasize again that we are not denying the clinical observations reviewed by Parrott, but conclude that the effects seen cannot be ascribed solely to the effects of MDMA, as he seems to be proposing. We also repeat our contention that MDMA in combination with other drugs may induce neurotoxicity and this could be said to be supported by the clinical studies quoted by Parrott.Finally, we can but assume that Parrott concurs with our principal conclusion that ‘the doses currently being used to investigate the possible therapeutic benefits of MDMA are unlikely to produce any severe acute or importantly any long-term neurotoxic damage in the human brain’ as he used such a dose (100 mg or approximately 1.4 mg·kg ⁻¹) in one of his recent studies in human volunteers (Parrott et al., 2011).     

The Healthy Worker Effect and Nuclear Industry Workers

The linear no-threshold (LNT) dose-effect relationship has been consistently used by most radiation epidemiologists to estimate cancer mortality risk. The large scattering of data by International Agency for Research on Cancer, IARC (Vrijheid et al. 2007; Therry-Chef et al. 2007; Cardis et al. 2007), interpreted in accordance with LNT, has been previously demonstrated (Fornalski and Dobrzyński 2009). Using conventional and Bayesian methods the present paper demonstrates that the standard mortality ratios (SMRs), lower in the IARC cohort of exposed nuclear workers than in the non exposed group, should be considered as a hormetic effect, rather than a healthy worker effect (HWE) as claimed by the IARC group.     

Themed section

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This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2This is the first themed issue on new developments in opioid pharmacology published by British Journal of Pharmacology (BJP). It is a bumper issue, with 39 papers, including 17 topical reviews. The issue emerged from invited review submissions by speakers at the International Narcotics Research Conference (INRC) held in Cairns, Australia from 14–18 July 2013, along with open submissions from attendees, and articles freely submitted following a call for papers. The meeting was sponsored in part by BJP and the British Pharmacological Society. INRC has been the major international meeting on opioid research for more than 40 years (see http://www.inrcworld.org/history.htm). Invited presentations at the 2013 meeting were largely focused on novel mechanisms of opioid receptor function and systems that are developing novel therapeutic avenues that could improve the clinical profile of opioids. In their International Union of Basic and Clinical Pharmacology (IUPHAR) review, Cox et al. (2015) discuss nomenclature recommendations for opioid receptors. Most papers in the themed issue conform to these recommendations.It is very difficult to separate therapeutic actions of opioids such as analgesia from serious adverse effects including (potentially lethal) respiratory depression, constipation, somnolence, tolerance and addiction because most are mediated by the opioid μ-receptor (MOPr). The developments discussed in the themed issue explore current knowledge of new pharmacological understanding of MOPr and its interactions other opioid receptors that could be exploited in future drug development to reduce these adverse effects. In its current state, the opioid therapeutic armamentarium has only just begun to exploit novel pharmacological mechanisms such as hetero-oligomer formation, ligand bias, allostery and synergy with other receptor systems, including other opioid receptors.The INRC meeting was opened with the traditional Founders Lecture delivered by Graeme Henderson (Henderson, 2015). The Founders Lecture honours the contributions of individuals who have a made a sustained and substantial contribution to the science upon which the conference is based. Graeme is certainly one of those. Graeme was the first to show in 1980 that opioids directly inhibit CNS neurons via hyperpolarization (Pepper and Henderson, 1980) which was later shown to be due to potassium channel activation. At the time of his seminal work, the predominant thinking was that morphine acted much like a local anaesthetic, simply blocking nerve conduction. His review reflects the progress made since then and the unanswered questions from an electrophysiologist''s perspective.A potential opportunity to exploit functional selectivity is development of heteromer selective opioids. Since the ground-breaking work of Lakshmi Devi suggesting that different opioid receptor types can form heteromers in heterologous expression systems there has been an extensive search for their presence and function in the central nervous system. The review by Massotte (2015) critically evaluates the evidence required to establish existence of heteromers in vivo. One of the crucial pieces of evidence is co-expression of the potential partner GPCRs in the same neuron. Massotte (2015) appraises the evidence for this and introduces her own studies of co-localization of MOPr and the opioid δ-receptor (DOPr) using knock-in mice that express both MOPr fused with a red fluorescent protein (mCherry) and DOPr fused with eGFP. The restricted colocalization in the CNS suggests potential for opioid drugs that selectively target MOPr-DOPr heteromers, moreover the general expression in lower brain regions involved in nociception indicates the potential for heteromer selective analgesics. Of course co-localization does not establish the existence of functional heteromers. Massotte discusses this and the review by Gendron et al. (2015) also touches on the question. The review by Fujita et al. (2015) further discusses the evidence for potential heteromer formation among opioid receptors or between opioid receptors and other GPCRs, revealing extensive potential for heteromer formation.Multiple opioid receptors expressed in a single cell may interact as heterodimers or, alternatively, modulate the surface expression and function of the other partner. Zhang et al. (2015) review the evidence that MOPr and DOPr interact in small dorsal root ganglion neurons and that the interaction is modulated by neuronal activity and morphine tolerance. This may begin to explain the widely published findings that DOPr antagonists can suppress morphine antinociceptive tolerance. Other reviews (e.g. Gendron et al., 2015) and research papers, e.g. Ong et al. (2015) also address this theme.Biased signaling and allostery have emerged as properties of many GPCRs that may provide opportunities to limit side effects. Biased opioid agonists that select for G-protein signaling in preference to β-arrestin pathways are in clinical development as analgesics with reduced side effects. Based on the plenary lecture from Arthur Christopoulos on bias and allostery, Thompson et al. (2015) provide an introduction to mechanisms of bias at opioid receptors focusing on MOPr with a detail review of the issues that must be considered in quantification of bias. The DOPr is also a potential target for pain management, particularly in neuropathic pain. Gendron et al. (2015) have comprehensively reviewed evidence for physiological functions of DOPr, including its potential for biased signaling, as well as the role of trafficking and surface expression of the receptor and potential interacting proteins involved in its regulation. Charfi et al. (2015) review different approaches to identify and quantify ligand-dependent bias at DOPr and review different types of experimental and analytical confounds in these analyses.Allosteric modulators have been reported for a range of GPCRs but until very recently none were known for opioid receptors. Burford et al. (2015) review the principles of positive, negative and ‘silent’ (neutral antagonists at the allosteric site) allosteric modulation in the context of their exciting recent discovery of allosteric modulators of MOPr, particularly positive allosteric modulators (PAMs) that enhance the activity of orthosteric MOPr agonists. PAMs of MOPr have the potential to enhance the effects of endogenously released opioids or low doses of opioid orthosteric agonists. The authors speculate on the potential advantages that a PAM approach might bring to the design of novel therapeutics for pain that may avoid the side effects currently associated with opioid therapy. The further development of PAMs and biased PAMs has great potential to contribute to pain therapy, perhaps in ways that have not been considered previously.Analgesics such as tramadol and more recently tapentadol exploit therapeutic interactions between opioid and other neurotransmitter systems. Synergistic interactions improve the therapeutic profile of opioids by limiting the degree of stimulus of the opioid system required to produce pain relief. Chabot-Doré et al. (2015) comprehensively review evidence for the best established interactions between α₂-noradrenergic agonists and both MOPr, and DOPr to provide pain relief in animal models. Sadeghi et al. (2015) describe additive mechanisms underlying the action of tapentadol in brain neurons.Development of tolerance is one of the major limitations of long-term opioid treatment. Understanding the mechanisms of MOPr regulation is thought to be crucial for understanding and potentially developing strategies to limit tolerance. Coordinated phosphorylation of C-terminal serine and threonine residues on MOPr plays a crucial role in the initial steps and perhaps sustained mechanisms of MOPr regulation, arrestin binding and endocytosis. Stefan Schulz''s group review their pioneering work (Mann et al., 2015) on the development and use of phospho-site specific antibodies to study homologous and heterologous MOPr regulation, the latter mediated by protein kinase C phosphorylation of MOPr. This could provide an explanation for the protein kinase C (PKC)-mediated desensitization of MOPr by morphine, when PKC has been activated, as observed in a range of cells (Henderson, 2015). However, the research paper of Arttamangkul et al. (2015) suggests the effects of PKC-inhibitors on MOPr may be indirect. Understanding the relevance of different phosphorylation sites and regulation of MOPr is very important because many splice variants and some of the polymorphisms of human MOPr involve this region of the receptor with potential implications for sensitivity to opioid analgesics, tolerance and addiction. Knapman and Connor (2015) comprehensively review the evidence for functional implications of human MOPr polymorphisms and a research paper in the themed issue (Cooke et al., 2015) examines the effects of one of these polymorphisms, L83I, on MOPr endocytosis in detail. Several of the submitted research papers in the themed issue further address mechanisms of MOPr regulation after chronic treatment with morphine (e.g. Connor et al., 2015; Macey et al., 2015). The research paper by Lowe and Bailey (2015) adds to the evidence that the mechanisms of MOPr desensitization in nerve terminals differ from those in the soma.The important role of the DOPr in mechanisms of tolerance and dependence to MOPr agonists and addiction related mechanisms is discussed in a number of papers that highlight the as yet unrealised therapeutic potential of DOPr drugs for addiction management. Comprehensive review and research papers by Laurent et al. (2015a,b) comment on the role of forebrain MOPr and particularly DOPr in reward and decision making. The main finding that long-term translocation of DOPr to the surface of cholinergic interneurons in the nucleus accumbens shell is associated with the selection and execution of goal-directed actions is particularly interesting although the cellular and molecular mechanisms involved are not yet understood. The review by Klenowski et al. (2015) comprehensively addresses the role of DOPr in addiction to a range of drugs. Baimel et al. (2015) discusses the interactions between the orexin/hypocretin system and opioids in brain regions related to addiction and potential for modulation addiction to opioids and other drugs.Therapeutic actions and adverse effects of opioids are not limited to analgesia or other nervous system actions. Reviews and research papers arising from the INRC symposium on ‘Opioids in Non-Neuronal Cells’ provide a perspective on actions not often considered by those working in the CNS. There is considerable interest and some controversy concerning the influence of opioid therapeutics on tumour progression. Yamamizu et al. (2015) discuss evidence and mechanisms whereby opioid κ-receptor (KOPr) agonists are anti-angiogenic so may have tumour suppressing properties. Morphine is commonly used in cancer pain management but there have been concerns that the drug may adversely influence post-operative cancer recurrence and metastasis. Afsharimani et al. (2015) provide a critical review of the validity of animal models designed to evaluate the effect of morphine on tumour growth and metastasis and suggest ways to improve current approaches. Another noteworthy action of opioids on non-neuronal cells includes the influence of DOPr receptor agonists on cutaneous wound healing (Bigliardi et al., 2015).Ultimately, the value of much of the knowledge of novel opioid mechanisms in the themed issue will be its translation into clinical practice. Avoiding tolerance and dependence, severe side effects and improving efficacy in chronic pain conditions all seem possible but there is a long way to go. For example, careful meta-analyses of weak and strong opioid use in chronic non-cancer pain (Reinecke et al., 2015) found only modest trends for efficacy of opioids and no evidence to support the sole or preferential use of opioids. Hopefully drugs exploiting novel opioid mechanisms will be better. Opioid agonists and antagonists also have an important place in management of addictions. For reviews of opioid treatments for addiction in humans the reader is referred to the recent issue of British Journal of Clinical Pharmacology on Addiction (2014, vol 77, Issue 2. Pp 225–400). In particular, articles by Bell (2014) and Garcia-Portilla et al. (2014) on maintenance treatments for opioid addiction and sustained release naltrexone for the management of opioid dependence (Kunøe et al., 2014).Current opioid therapeutics for chronic pain management and addiction are problematic and still largely rely on drugs developed many decades ago. There is hope that findings in this themed issue will lead to the development of new generation opioid analgesics with improved clinical profiles.     

Found in translation? Commentary on a BJP themed issue about animal models in neuropsychiatry research

This themed issue of Br J Pharmacol is dedicated to the utility and needs of animal models in psychiatry research. The following articles document strengths and weaknesses, indicate areas where better models are sorely needed and provide examples where pharmacological studies may result in mechanistic breakthrough and aid in drug development. In addition, complicating factors both in disease and treatment strategies are canvassed, such as sex differences, genetic and environmental influences. While not exhaustive, the intention was to use a number of exemplars to stimulate discussion around how animal models can aid in improving our understanding and treatment of many devastating conditions.

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This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20Karl Menninger once said ‘unrest of spirit is a mark of life’, acknowledging the widespread occurrence of psychiatric disorders. According to the World Health Organisation 2014 Global Health Estimates, ‘mental and behavioural disorders’ make up 7.3% of all disability adjusted life years (DALYs) while ‘neurological conditions’ add an additional 2.9% of all DALYs. Tellingly, unipolar depression sits within the top 10 of all causes (see http://www.who.int/healthinfo/global_burden_disease/estimates/en/index2.html). As stated in the 2013 World Health Report ‘The creativity and skills of researchers should be used to strengthen investigations not only in academic centres but also in public health programmes, close to the supply of and demand for health services’(WHO, 2013). The ever-growing incidence rates for psychiatric disorders and the need for better therapeutic approaches make this somewhat generalized statement a sobering reality check. Accordingly, we have dedicated a special issue of the British Journal of Pharmacology to scrutinize animal models in the psychiatry domain and to provide some direction for the field. Better models with better validity will undoubtedly assist in knowledge advances that may facilitate drug development. One should however recognise that modelling psychiatric disorders with constellations of symptomology and comorbidity is a difficult, often impossible, task. Nevertheless, advances in modeling aspects of disorders are happening and will continue to be refined going forwards.Parenthood is a time of immense change. In addition to obvious lifestyle changes (and lack of sleep!), there is substantial physiological and behavioural plasticity. The opening review of this issue details numerous manipulations that have been used in an attempt to model aspects of post-partum mood and anxiety disorders (Perani and Slattery, 2014). For example, stress, diet, deliberate hormone fluctuation with phantom pregnancy, separation and selective breeding have all been examined in this regard. As indicated by Perani and Slattery, a major drawback in many of the studies has been a relative lack of end-point readouts and therefore a need going forward is to more broadly characterise the consequences of an individual manipulation. In addition, developing models that incorporate findings from genetic association studies is also clearly warranted.There is a recent appreciation that adolescence maybe a particularly vulnerable time for the onset of certain psychiatric diseases (O’Connor and Cryan, 2014). As highlighted by Ganella and Kim, anxiety disorders often present in childhood and early adolescence (Ganella and Kim, 2014), suggesting that early diagnosis and intervention may have long-lasting benefit. Indeed fear learning has clear developmental modulation, as has the ‘therapeutic’ process of extinction. Interestingly, in juvenile subjects it is suggested that extinction may not involve new learning but rather may be a form of erasure. This would then argue for behavioural therapies in children as soon as possible after diagnosis of an anxiety disorder (Ganella and Kim, 2014). In older subjects, extinction is well-established as an active learning process and is widely studied as a translational behavioural intervention for anxiety. Thus, there is a considerable literature detailing conditioned fear and the extinction of conditioned fear. Here, Bukalo and colleagues provide a review of the pertinent circuitry for extinction of conditioned fear and a wide range of pharmacological intervention strategies (Bukalo et al., 2014). Indeed, they conclude that despite the obvious major challenges that beset all CNS drug development, systems neuroscience advances should ultimately identify molecular targets for new therapeutics. Nevertheless, this should be paralleled by deeper investigation of behavioural approaches which would likely reach patients sooner than a new chemical entity. As with anxiety, depression also presents with cognitive impairment. The issue of cognitive affective biases in depression, and the ability to model these in animals is detailed along with pharmacological validation studies (Hales et al., 2014). While these approaches to depression are in relatively early days, studies to date suggest this as a worthy line of enquiry, potentially enabling causal mechanistic studies as well as playing a part in drug development.In addition to anxiety disorders, extinction has also been used in the context of addiction research and treatment. Perry and colleagues present a discussion of how cues and contextual stimuli regulate drug use and also relapse (Perry et al., 2014). Indeed, in the case of relapse prevention, they argue how the cues themselves can become treatment targets via active extinction training in a relevant contextual environment. This opens an arena for small molecule drugs to be employed to facilitate the learning process behind cue extinction procedures and thereby strengthen the ongoing protection against relapse. Addiction is a complex, multi-faceted disorder and often shares comorbidity with other psychiatric disorders. The relationship between impulsivity and addiction is addressed by Jupp and Dalley (2014), and examines whether treating impulsivity can also impact upon drug-seeking. Aberrant eating patterns are increasingly likened to addiction disorders due to common psychological and anatomical systems being implicated in both disorders. There are a number of models that recapitulate facets of both binge eating and anorexia nervosa (van Gestel et al., 2014). In both cases, drugs targeting monoamine systems are a major focus of preclinical and clinical investigations.In 2009, the incidence of eating disorders in the UK was 164.5 per 100,000 girls aged 15–19, almost 10-fold the number for boys of the same age (Micali et al., 2013). This exemplar highlights the need to consider sex when modeling disorders in animals. Indeed the National Institutes of Health in the US have recently unveiled policies to ensure that preclinical research they fund considers females and males in all animal studies (Clayton and Collins 2014). Two reviews address this issue and highlight how sex can interact with genetic, environmental and pharmacological mechanisms in affective disorders (Kokras and Dalla, 2014; Joel and Yankelevitch-Yahav, 2014). Indeed, it is argued that ‘sexual dimorphism’ should be abandoned and further that ‘sex differences’ are reconsidered as ‘sex interactions’ (Joel and Yankelevitch-Yahav, 2014). In a similar manner, McOmish and colleagues address critical issues of face, construct and predictive validity in animal models with the complicating factors of gene x environment interactions that are a feature of our life (McOmish et al., 2014).As mentioned above, modeling of complex behavioural disorders in animals is fraught with danger. Even if the aetiology of the human condition is known, making a robust animal model can be difficult. Consider then the task of modeling a human condition for which the aetiology is unknown! Migraine is an example of a chronic disorder for which the pathophysiology in humans is still equivocal, yet there are a number of models that have helped our understanding of specific aspects of headache and migraine (Erdener and Dalkara, 2014). Indeed, this demonstrates the need for forward and reverse translation in all animal modelling, where advances in human studies (such as imaging) can be applied to the pertinent models and findings in such models can be tested in human studies.This special issue began with post-partum disorders and wraps up with a discussion of post-stroke depression (Kronenberg et al 2014). Depression is common after stroke, and those who succumb typically show worse outcomes. Evidence is presented to show how in rodent models, fluoxetine and citalopram have shown efficacy not only to reduce post-stroke ‘depression’ but have also improved other outcomes, such as lesion size and extrafocal degeneration. This is complemented by positive trials of fluoxetine in human stroke patients, irrespective of depression status (Kronenberg et al 2014).This Special Issue therefore provides food for thought regarding conceptualizing and putting into practice animal models that have relevance in psychiatric research and drug development strategies. The purpose was not to cover every disorder, but rather highlight some examples that will hopefully stimulate debate within the field. Research areas that have been relatively neglected to date are particularly focused on. Readers are also referred to a previous Special Issue in the Journal (Green et al., 2011) that focused on other disorders such as schizophrenia, anxiety and Alzheimer’s Disease (Jones et al., 2011; Cryan & Sweeney, 2011, Van Dam and De Deyn, 2011). A major challenge going forwards is to not only incorporate new technologies and methodologies, but to constantly update and back/forward translate when appropriate. Insodoing, this approach may help us to further identify the cause(s) and possible treatments of many debilitating conditions.     

A Quantitative Evaluation of Medication Histories and Reconciliation by Discipline

Background/Objective:

Medication reconciliation at transitions of care decreases medication errors, hospitalizations, and adverse drug events. We compared inpatient medication histories and reconciliation across disciplines and evaluated the nature of discrepancies.

Methods:

We conducted a prospective cohort study of patients admitted from the emergency department at our 760-bed hospital. Eligible patients had their medication histories conducted and reconciled in order by the admitting nurse (RN), certified pharmacy technician (CPhT), and pharmacist (RPh). Discharge medication reconciliation was not altered. Admission and discharge discrepancies were categorized by discipline, error type, and drug class and were assigned a criticality index score. A discrepancy rating system systematically measured discrepancies.

Results:

Of 175 consented patients, 153 were evaluated. Total admission and discharge discrepancies were 1,461 and 369, respectively. The average number of medications per participant at admission was 8.59 (1,314) with 9.41 (1,374) at discharge. Most discrepancies were committed by RNs: 53.2% (777) at admission and 56.1% (207) at discharge. The majority were omitted or incorrect. RNs had significantly higher admission discrepancy rates per medication (0.59) compared with CPhTs (0.36) and RPhs (0.16) (P < .001). RPhs corrected significantly more discrepancies per participant than RNs (6.39 vs 0.48; P < .001); average criticality index reduction was 79.0%. Estimated prevented adverse drug events (pADEs) cost savings were $589,744.

Conclusions:

RPhs committed the fewest discrepancies compared with RNs and CPhTs, resulting in more accurate medication histories and reconciliation. RPh involvement also prevented the greatest number of medication errors, contributing to considerable pADE-related cost savings.Key Words: admission, evaluation study, discharge, medication reconciliationObtaining medication histories and conducting medication reconciliation are challeng ing tasks with the advent of new molecular entities and orphan drugs.¹ As Franklin reported, “Patients who once came into the [physician] office carrying their medications in a purse, or pocket, now need a shopping bag.”² The importance of accurate medication histories cannot be overemphasized; nearly 27% of all hospital prescribing errors originate from incorrect admission medication histories, over 70% of drug-related problems are only discovered through patient interview, and more than 50% of discharge discrepancies are associated with admission discrepancies.^3–6In 2010, an Institute of Medicine report estimated that if hospitals prevented adverse drug events (pADEs) and redundant tests, the associated cost savings would be nearly $25 billion annually.⁷ One organization decreased inpatient care costs by 30% when no medication reconciliation errors were reported over 24 months. ⁷Multiple organizations have supported medication reconciliation to improve quality of care, reduce preventable hospital admissions and readmissions, and decrease the incidence of adverse health care- associated conditions.^8–11 Although The Joint Commission does not indicate the discipline to perform this role, evidence supports the role of registered pharmacists (RPhs), pharmacy students, and pharmacy technicians in collecting accurate medication histories. RPhs should be involved when high-risk medications are identified, more than 5 medications are reported, or patients are elderly.^6,8,11–40 Therefore, our primary study objective was to compare inpatient medication histories and reconciliation processes across disciplines and to evaluate the nature of discrepancies using a novel method.     

Renoprotective effects of metformin

Metformin as a biguanid drug entered to the market 50 years ago and now is generally recommended as the first-line treatment in type 2 diabetes, especially in overweight patients, however in recent years new indications for its use have emerged . It improves peripheral and liver sensitivity to insulin, reduces basal hepatic glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases hunger and causes weight reduction.Recently, much attention has been made toward the possible kidney protective efficacy of metformin. Recent studies have proven that metformin, possesses antioxidant properties, too.Dear Editor-in-Chief,Metformin as a biguanid drug entered to the market 50 years ago and now is generally recommended as the first-line treatment in type 2 diabetes, especially in overweight patients, however in recent years new indications for its use have emerged [1-3]. It improves peripheral and liver sensitivity to insulin, reduces basal hepatic glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases hunger and causes weight reduction [1,3,4]. Recently, much attention has been made toward the possible kidney protective efficacy of metformin. Recent studies have proven that metformin, possesses antioxidant properties, too [1,5]. Reduction of apoptosis, induced by oxidative stress, in endothelial cells and prevention of vascular dysfunction was found with metformin treatment [1,5,6]. Previously Morales et al. showed that gentamicin-induced renal tubular damage is attenuated by metformin [7]. To better evaluate the ameliorative effect of metformin against gentamicin tubular toxicity, we conducted a study on male Wistar rats [8]. In this study, we found, the preventive property of metformin on gentamicin-induced acute kidney injury. Hence, it might be beneficial in patients under treatment with this drug [8]. Recently, Taheri et al., found, the ameliorative property of metformin against unilateral ischemia–reperfusion induced injury in rats [9], which is in accord with our findings. More recently, to test the efficacy of co-administration of garlic extract and metformin for prevention of gentamicin–renal toxicity in Wistar rats, we conducted another study on 70 male rats [10]. The result of this study indicates that metformin and garlic or their combination has both curative and protective effects against gentamicin nephrotoxicity. Hence, garlic extract could safely be used together with metformin to increase the antioxidant potency to ameliorate gentamicin-tubular toxicity [10]. The well-known enzyme, AMP-activated kinase (AMPK), is associated with the pleiotropic actions of metformin [11]. This enzyme regulates cellular and organ metabolism [5,6,11]. AMPK is a phylogenetically conserved serine/threonine protein kinase imagined as a fuel gauge monitoring systemic and cellular energy condition [5,6,11] and plays an important role in protecting cellular functions under energy-restricted circumstances [5,6,11]. Various data indicates that AMPK activation by metformin is secondary to its effect on the mitochondria as the primary target of this agent [5,6,11]. Recent findings have revealed the mitochondrial effects of metformin [5,6,11,12]. Indeed, there is evidence that, when it is used alone, the advantageous effect of metformin may be due to its mild inhibition of the mitochondrial respiratory chain [5,6,11,12]. It is also evident that metformin treatment, significantly attenuates the increase in malondialdehyde and total reactive oxygen species generation and restores the decrease in both enzymatic and non-enzymatic antioxidants [5], thus, poses the ameliorative effects against toxic effects to the renal tubules [6,11-14], as we observed in the mentioned studies. However, the main question is, whether these experimental findings are applicable in clinical studies. We are mostly unanimous to use metformin as a first-line glucose-lowering agent [14-19]. However, it cannot be given to a proportion of patients with type 2 diabetes due to various contraindications that could lead to an increased risk of lactic acidosis [1,2,16,17]. Scientists emphasize that it must be used with caution in estimated glomerular filtration rates of below 60 mL/minute and discontinued when estimated glomerular filtration rate is less than 30 mL/minute [1,2,16,17]. Metformin-associated lactic acidosis is a severe metabolic disorder with high mortality and in severe cases patients may need renal replacement therapy [19]. However, risk of metformin-associated lactic acidosis could be decreased by avoiding metformin use in patients with high risk of sepsis, renal impairment, hypovolemia, reduced kidney capacity such as old age patients [19]. Nevertheless, in these conditions, metformin may indeed act as an ''innocent bystander'' [1,2,16,17,19]. A recent review by Papanas et al. remarking on the relationship between metformin and cardiac insufficiency revealed that metformin might even reduce the risk of cardiac failure morbidity and mortality in diabetics [20]. To find the advantage of adjunct metformin and insulin therapy in the management of glycemia in critically ill patients, Mojtahedzadeh et al. studied thirty three traumatized adult patients who were admitted to the hospital. Patients were randomly assigned to receive one of three protocols including intensive insulin monotherapy (A), metformin monotherapy (B), and intensive insulin therapy in combination with metformin (C) to maintain blood glucose level between 80–120 mg/dl. They found that metformin was able to reduce insulin requirements in glycemic management of critically ill patients independent of its plasma concentration. They concluded that metformin was effective to reverse insulin resistance without induction of lactic acidosis [21]. On the other hand, it is possible that the use of metformin would be favorable in many with chronic renal failure according to the advantages linked with lessening of metabolic syndrome and cardiovascular protection. The actuality of severe metformin-induced lactic acidosis in the absence of chronic kidney failure raises the question of limitation of its use in these patients [16,20]. Diabetic nephropathy is one of the most important complications of diabetes mellitus [22-26] and metformin has been widely used for the treatment of type 2 diabetes [17-19]. Kim et al. conducted a study using metformin for spontaneously diabetic rats for 17 weeks. They found that treatment of diabetic rats with metformin restored podocyte loss. They suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by metformin, through the repression of oxidative injury [27]. Thus according to our results and those published by previous investigators, metformin protects against tubular injury by restoring the biochemical alterations and modulation of oxidative stress on the tubules. Furthermore, according to the study of Kim et al., metformin protects podocytes in diabetic nephropathy. While in diabetic nephropathy, there is also tubular cell injury [28-31] due to glycosuria. These findings can more potentiate the clinical use of metformin in the prevention of diabetic nephropathy [32-36]. In this regard, to understand the metformin kidney protective properties better, more experimental rat model or clinical studies are suggested.     

Value of Pharmacist Medication Interviews on Optimizing the Electronic Medication Reconciliation Process

Purpose:

Few studies have explored the impact of using different methods for obtaining accurate medication histories on medication safety. This study was conducted to compare the accuracy and clinical impact of pharmacist medication histories obtained by electronic medical record review (EMRR) alone with those obtained by direct interviews combined with EMRR.

Method:

This 18-week prospective study included patients who were admitted to the Inpatient Medicine Service at the study institution and who had a pharmacist-conducted medication reconciliation EMRR within 48 hours of hospital admission. A chart review was performed to collect data to determine whether differences existed in the number of discrepancies, recommendations, and medication errors between the EMRR alone group compared to the EMRR combined with the patient interview group.

Results:

Five hundred thirteen discrepancies were identified with the EMRR group compared to 986 from the combined EMRR and patient interview group (P < .001). Significantly more recommendations were made in the combination interview group compared to the EMRR alone group (260 vs 97; P < .001). Fewer medication errors were identified for the EMRR alone group compared to the combination interview group (55 vs 134; P < .001). The most common errors were omitted medications followed by extra dose/failure to discontinue therapy and wrong dose/frequency errors.

Conclusion:

Pharmacist-conducted admission medication interviews combined with EMRR can potentially identify harmful medication discrepancies and prevent medication errors.Key Words: medication reconciliation, pharmacist medication interviewsPatient safety is a national priority for The Joint Commission and the Institute of Medicine.^1–3 It has been estimated that 25% of medication-related injuries are related to preventable medication errors.^4–6 Many of these medication errors are related to unintentional medication discrepancies that occur during transitional points of health care, including hospital admissions, transfers, and discharge.^1,3,6–8 According to The Joint Commission, medication reconciliation is defined as “…the process of identifying the medications currently being taken by an individual.” ³ These medications are compared to newly ordered medications, and discrepancies are identified and resolved. Medication reconciliation is an essential process that health care systems need to implement to avoid unnecessary harm to patients related to medication errors. Approximately 46% of all medication errors and 20% of adverse drug events (ADEs) have been attributed to a lack of medication reconciliation.2,⁷ As a result, The Joint Commission mandated that institutions comply with the National Safety Goal 8 to “accurately and completely reconcile medications across the continuum of care” to prevent drug omissions, duplications, and drug interactions.³ Recently, The Joint Commission revised its Hospital National Patient Safety goals related to medication reconciliation and currently requires hospitals to “maintain and communicate accurate patient medication information.”³ To accomplish this standard, a current list of the patient’s outpatient medications will be obtained upon admission and then compared with the patient’s hospital medication orders in efforts to identify and resolve discrepancies.^1,3 At discharge, The Joint Commission recommends that patients should receive “written information on the medications” that the patients will be taking following discharge from the hospital and should receive patient education on the “importance of managing” their medication information.³Although The Joint Commission recommends that medication reconciliation should be performed at admission, the agency does not provide guidance for how health care institutions should effectively conduct this process. One strategy is to follow the Institute of Medicine’s recommendations to implement information technologies, including the use of electronic medical records and computerized physician order entry systems.^9,10 Ideally, the use of these technologies would facilitate the effectiveness and efficiency of performing chart reviews and, thereby, the medication reconciliation process. Another strategy is to obtain a medication history by directly interviewing the patient and/or the patient’s caregiver.⁹Studies have revealed that obtaining an accurate and complete medication history is an important step for initiating the medication reconciliation process.^6–21 Results from a review of 22 studies demonstrated that 27% to 54% of patients had at least one medication error on hospital admission.⁶ In particular, several studies have described the value of pharmacist-obtained medication histories.^6,13,15,16 These studies have demonstrated that pharmacists identified a higher number of medications or medication discrepancies compared to physicians and other nonphysician providers when obtaining medication histories. Other studies also demonstrate that pharmacist-initiated histories resulted in fewer medication errors^15,18 and ADEs.^11–13Despite these benefits, many health care institutions do not require that pharmacists routinely perform medication interviews as part of the medication reconciliation process, because of workload concerns and lack of pharmacy manpower.^6,15 Moreover, with the use of information technologies, the need to have pharmacists conduct interviews may not be necessary if pharmacists can obtain a complete and accurate medication list through electronic medical chart review. Few studies have explored the impact of using different methods for obtaining accurate medication histories on medication safety.^{9,22, 23} This study was conducted to compare the accuracy and clinical impact of pharmacist medication histories obtained by electronic medical record review (EMRR) alone with those obtained by direct interviews combined with EMRR.     

Repeated Social Stress Increases Reward Salience and Impairs Encoding of Prediction by Rat Locus Coeruleus Neurons

Stress is implicated in psychopathology characterized by cognitive dysfunction. Cognitive responses to stress are regulated by the locus coeruleus–norepinephrine (LC–NE) system. As social stress is a prevalent human stressor, this study determined the impact of repeated social stress on the relationship between LC neuronal activity and behavior during the performance of cognitive tasks. Social stress-exposed rats performed better at intradimensional set shifting (IDS) and made fewer perseverative errors during reversal learning (REV). LC neurons of control rats were task responsive, being activated after the choice and before reward. Social stress shifted LC neuronal activity from being task responsive to being reward responsive during IDS and REV. LC neurons of stressed rats were activated by reward and tonically inhibited by reward omission with incorrect choices. In contrast, LC neurons of stress-naive rats were only tonically inhibited by reward omission. Reward-related LC activation in stressed rats was unrelated to predictability because it did not habituate as learning progressed. The findings suggest that social stress history increases reward salience and impairs processes that compute predictability for LC neurons. These effects of social stress on LC neuronal activity could facilitate learning as indicated by improved performance in stressed rats. However, the ability of social stress history to enhance responses to behavioral outcomes may have a role in the association between stress and addictive behaviors. In addition, magnified fluctuations in LC activity in response to opposing behavioral consequences may underlie volatile changes in emotional arousal that characterize post-traumatic stress disorder.In response to acute stressors, neural systems that regulate the hypothalamic–pituitary–adrenal axis, autonomic function, behavior, and cognition are engaged in a coordinated manner to cope with the stressor and promote survival. Persistent or repeated activation of these stress systems as a result of chronic or repeated stress, or inappropriate activation of the systems in the absence of stress, is maladaptive and results in pathology (Chrousos and Gold, 1992; de Kloet et al, 2005; McEwen, 1998). Such maladaptive stress responses are thought to underlie symptoms such as hyperarousal, inappropriate fear, and attentional and cognitive dysfunctions that characterize certain psychiatric disorders (Gold and Chrousos, 2002). Interestingly, although many studies report impairment of cognitive processes by stressors, there are also reports of enhancement and these differences may depend on the specific stressor and the cognitive endpoint (Bondi et al, 2008; Butts et al, 2013; Graybeal et al, 2011; Lapiz-Bluhm et al, 2009; Thai et al, 2013). These differences underscore the complexity of effects of stress on neural circuits that regulate cognitive functions.The locus coeruleus–norepinephrine (LC–NE) system is a stress-response system that has been implicated in cognitive responses to stress and in stress-related psychopathology (Southwick et al, 1999; Valentino and Van Bockstaele, 2008; Wong et al, 2000). LC neurons are spontaneously active and their discharge rate is positively correlated to behavioral indices of arousal (Aston-Jones and Bloom, 1981b; Foote et al, 1980). Salient stimuli elicit a phasic activation of LC neurons that precedes orientation to the stimulus and this has implicated the system in attention (Aston-Jones and Bloom, 1981a; Berridge and Waterhouse, 2003; Foote et al, 1980). LC neuronal recordings in animals performing operant tasks indicate that phasic LC discharge is associated with focused attention and staying ‘on-task'', whereas high-tonic LC discharge is associated with labile attention and task disengagement (Aston-Jones and Cohen, 2005; Bouret and Sara, 2005; Sara, 2009). It has been suggested that this high-tonic mode of LC discharge facilitates cognitive flexibility (Aston-Jones and Cohen, 2005). Acute stressors and exposure to the stress-related peptide, corticotropin-releasing factor (CRF) bias LC activity towards a high-tonic state that may be adaptive in a dynamic environment with life-threatening challenges (Curtis et al, 2012; Valentino and Foote, 1987; Valentino and Wehby, 1988). Notably, certain doses of CRF improve extradimensional set-shifting performance during an attentional set-shifting task (AST), an endpoint of cognitive flexibility (Snyder et al, 2012). In contrast to the activating effects of acute stressors on LC neuronal activity, repeated social stress produces an enduring inhibition of rat LC discharge that is apparent several days after the last stressor (Chaijale et al, 2013). These findings are relevant to humans given that social stress is one of the most common human stressors. A similar enduring inhibition of LC activity occurs in rats exposed to a model of post-traumatic stress disorder that involves the administration of three consecutive stressors (George et al, 2013). It is unknown how this state of LC inhibition impacts on cognition.As cognitive dysfunction is thought to be one of the maladaptive consequences of repeated stress and the LC–NE system has been implicated in cognitive aspects of the stress response, the present study investigated the long-term effects of repeated social stress on LC activity recorded during the performance of an AST that assesses simple discrimination (SD), compound discrimination (CD), intradimensional set shifting (IDS), reversal learning (REV), and extradimensional set shifting. The results provided evidence that repeated social stress changes the relationship between LC neuronal activity and task performance, and renders LC neurons responsive to reward regardless of its predictability.     

Counteracting PINK/Parkin Deficiency in the Activation of Mitophagy: A Potential Therapeutic Intervention for Parkinson’s Disease

Parkinson’s Disease (PD) related genes PINK1, a protein kinase [1], and Parkin, an E3 ubiquitin ligase [2], operate within the same pathway [3-5], which controls, via specific elimination of dysfunctional mitochondria, the quality of the organelle network [6]. Parkin translocates to impaired mitochondria and drives their elimination via autophagy, a process known as mitophagy [6]. PINK1 regulates Parkin translocation through a not yet completely understood mechanism [7, 8]. Mitochondrial outer membrane proteins Mitofusin (MFN), VDAC, Fis1 and TOM20 were found to be targets for Parkin mediated ubiquitination [9-11]. By adding ubiquitin molecules to its targets expressed on mitochondria, Parkin tags and selects dysfunctional mitochondria for clearance, contributing to maintain a functional and healthy mitochondrial network. Abnormal accumulation of misfolded proteins and unfunctional mitochondria is a characteristic hallmark of PD pathology. Therefore a therapeutic approach to enhance clearance of misfolded proteins and potentiate the ubiquitin-proteosome system (UPS) could be instrumental to ameliorate the progression of the disease. Recently, much effort has been put to identify specific de-ubiquitinating enzymes (DUBs) that oppose Parkin in the ubiquitination of its targets. Similar to other post-translational modifications, such as phosphorylation and acetylation, ubiquitination is also a reversible modification, mediated by a large family of DUBs [12]. DUBs inhibitors or activators can affect cellular response to stimuli that induce mitophagy via ubiquitination of mitochondrial outer membrane proteins MFN, VDAC, Fis1 and TOM20. In this respect, the identification of a Parkin-opposing DUB in the regulation of mitophagy, might be instrumental to develop specific isopeptidase inhibitors or activators that can modulate the fundamental biological process of mitochondria clearance and impact on cell survival.     

Commentary on Using LNT for Radiation Protection and Risk Assessment

An article by Jerome Puskin attempts to justify the continued use of the linear no-threshold (LNT) assumption in radiation protection and risk assessment. In view of the substantial and increasing amount of data that contradicts this assumption; it is difficult to understand the reason for endorsing this unscientific behavior, which severely constrains nuclear energy projects and the use of CT scans in medicine. Many Japanese studies over the past 25 years have shown that low doses and low dose rates of radiation improve health in living organisms including humans. Recent studies on fruit flies have demonstrated that the original basis for the LNT notion is invalid. The Puskin article omits any mention of important reports from UNSCEAR, the NCRP and the French Academies of Science and Medicine, while citing an assessment of the Canadian breast cancer study that manipulated the data to obscure evidence of reduced breast cancer mortality following a low total dose. This commentary provides dose limits that are based on real human data, for both single and chronic radiation exposures.Jerome Puskin’s perspective on the use of the linear no-threshold (LNT) assumption for radiation protection and risk assessment (Puskin 2009) raises the question: does the U.S. Environmental Protection Agency (EPA) really protect the public or only the established worldwide practice of protecting people from radiation, which costs hundreds of billions of dollars a year? EPA exposure limits are many orders of magnitude below the levels where there is evidence of harm (Jaworowski 1999, Sanders 2010), leading to inappropriate restrictions on the use of nuclear energy to generate electricity and on the use of ionizing radiation in medicine to diagnose serious illnesses. Harmless and beneficial doses should not be regulated. Living organisms can adapt and have adapted to natural radiation, which ranges in intensity from about 0.1 to more than 70 rem per year.The assumptions and models employed by the EPA are not based on modern biological science. The LNT assumption of radiation carcinogenesis, formulated more than 50 years ago, was originally based on experiments that were carried out on fruit flies in the mid-1920s (Muller 1954). At that time, it appeared to be reasonable for estimating cancer risk because this risk was considered to be proportional to mutation rate, which was found to be proportional to radiation dose in high dose ranges. Radiobiologists now know that organisms have defenses against DNA damage and that these can be stimulated by low doses. Although the LNT assumption is still widely accepted, it does not reflect reality, and its continued use is causing great social harm, particularly by constraining wider use of nuclear energy and CT diagnostic scans (Scott et al. 2008).Since the mid-1980s, the Central Research Institute of the Electric Power Industry in Japan has been carrying out remarkable studies on health effects of radiation. Their recent research has demonstrated a threshold at about 1 Gy^† for x-ray-induced DNA mutations in fruit flies and activation of repair by low-dose irradiation, which reduced background mutation (Koana et al. 2004, Koana et al. 2007). Gamma ray irradiation of fruit flies at a dose rate of 22.4 mGy per hour reduced lethal mutation frequency below that in the control flies (Ogura et al. 2009), as shown in Figure 1. The original basis for the LNT assumption has therefore been shown to be invalid.Open in a separate windowFIGURE 1In selecting reports from scientific advisory bodies, the EPA appears to have omitted Scientific Annex B in UNSCEAR 1994, which assessed 192 scientific publications that provide evidence of beneficial health effects of low doses or low dose rates of radiation. The EPA also did not select the report of the French Academy of Science (Académie des sciences 1997), or the joint report of the French Academies of Medicine and Science (Tubiana et al. 2005) both of which raise doubts about the validity of the LNT hypothesis at low doses. A more recent publication in Radiology points out that the LNT relationship is inconsistent with data (Tubiana et al, 2009).Lauriston Taylor, former president of the National Council on Radiation Protection and Measurements (Taylor 2010), denounced the use of a procedure to calculate the expected number of deaths per year resulting from x-ray diagnoses, as follows (Taylor 1980): “These are deeply immoral uses of our scientific heritage.” Unfortunately, this advice was ignored when scientists assessing the Chernobyl accident projected up to 28,000 excess cancer deaths using the LNT assumption and high-dose Hiroshima-Nagasaki data (Catlin et al. 1987). “No one has been identifiably injured by radiation while working within the first numerical standards set by the ICRP in 1934 (safe dose limit: 0.2 rad per day)” (Taylor 1980). Yet members of the U.S. public are limited to 0.5 rem per year.The LNT methodology, as it is generally applied by radiation protection organizations, was tested by a comprehensive study of radon levels in U.S. homes. It failed the test (Cohen 1995).Puskin cites the Howe and McLaughlin 1996 assessment of the Canadian breast cancer study of tuberculosis (TB) patients (Miller et al. 1989) as support for the LNT model, which has been fitted to the Hiroshima-Nagasaki life span study data. However, this assessment manipulated the breast cancer mortality data in a manner that concealed the evidence of protection by low doses that Edward Webster revealed in his Lauriston S. Taylor lecture to the NCRP (Webster 1992). Figure 2 shows the configuration for the fluoroscopy examinations. Figure 3 is Webster’s graph of the Miller et al. data for patients treated for TB between 1930 and 1952. The Nova Scotia patients received a breast dose of 50 mGy (5 rad) per exposure. The patients in the other provinces received a dose of 2 mGy per exposure. Webster fitted straight lines to the high dose data points, and he extended the lines to the breast cancer death rate of the unexposed subjects. The number of exposed subjects in the “other provinces” is 12,094, while the number of unexposed subjects is 17,557. The graph suggests that women who received a total breast dose of 0.15 Gy (15 rad) have a death rate one-third lower than the breast cancer death rate for unexposed women.Open in a separate windowFIGURE 2Open in a separate windowFIGURE 3The Howe-McLaughlin study combined three low-dose data ranges, averaging risk over the wide dose interval 0.01 to 0.49 Gy, and thus obscured the evidence that low doses of radiation provide the benefit of reduced breast cancer mortality. This evidence is highly relevant to the risk of mammography performed repeatedly over a long period of time. This manipulation of low-dose data is one of several “tricks” that epidemiologists have been using over the years to obscure evidence of radiation hormesis (Scott et al. 2008, Scott 2008).A recent review of nuclear energy and health (Cuttler and Pollycove 2009) concludes: “Based upon human data, a single whole body dose of 150 mSv (15 rem) is safe. The high background of 700 mSv/year (70 rem/year) in the city of Ramsar, Iran is also a safe dose limit for continuous chronic exposure. Both dose limits are also beneficial.”     

The Dorsal Agranular Insular Cortex Regulates the Cued Reinstatement of Cocaine-Seeking,but not Food-Seeking,Behavior in Rats

Prior studies suggest that the insular cortex (IC), and particularly its posterior region (the PIc), is involved in nicotine craving and relapse in humans and rodents. The present experiments were conducted to determine whether the IC and its different subregions regulate relapse to cocaine-seeking behavior in rats. To address this issue, male Sprague–Dawley rats underwent cocaine self-administration followed by extinction training and reinstatement tests. Before each reinstatement, the PIc or the more anterior dorsal agranular IC (AId) was inactivated to determine their roles in the reinstatement to cocaine seeking. In contrast to the nicotine findings, PIc inactivation had no effect on cue-induced reinstatement for cocaine seeking. However, AId inactivation reduced cued reinstatement while having no effect on cocaine-prime reinstatement. AId inactivation had no effect on reinstatement of food-seeking behavior induced by cues, a food-prime, or cues+food-prime. Based on previous work hypothesizing a role for corticotropin-releasing factor (CRF) in the IC during craving and relapse, a subsequent experiment found that CRF receptor-1 (CRF1) blockade in the AId similarly reduced cued reinstatement. Our results suggest that the AId, along with CRF1 receptors in this region, regulates reinstatement to cocaine seeking, but not food seeking, depending on the type of reinstatement, whereas PIc activity does not influence cue-induced reinstatement.Studies examining the reinstatement of cocaine-seeking behavior have found that the medial prefrontal cortex (PFC) is a critical driver of such behavior (LaLumiere et al, 2012; McFarland et al, 2003), yet considerably less attention has focused on the roles of the lateral PFC in regulating cocaine seeking. However, recent work suggests that the insular cortex (IC), a region in the lateral PFC, may be critically involved in craving and relapse (Naqvi and Bechara, 2010). Human neuroimaging studies have consistently found that drug-associated cues elicit IC activity in participants across multiple types of drug addiction (Brody et al, 2002; Kilts et al, 2004; Myrick et al, 2004). These observations led to a study demonstrating that insula lesions in humans produce significant disruption in nicotine addiction (Naqvi et al, 2007), a finding that has been confirmed in subsequent research (Gaznick et al, 2014) and has led to increased attention to this region with regard to its role in addiction.Experiments using rodent models indicate that reversible inactivation of an IC subregion known as the posterior IC (PIc; also known as the granular IC), as well as electrical stimulation of the IC, reduces both nicotine self-administration and reinstatement in rats (Forget et al, 2010; Pushparaj et al, 2013). In contrast, the more anterior subregions of the IC, including the anterior dorsal agranular IC (AId), appear to drive amphetamine place preference (Contreras et al, 2012). Although the role of the IC has not been extensively investigated with regard to cocaine-seeking behavior, prior work has found that cocaine self-administration increases expression levels of the plasticity-associated gene Arc, notably, in the AId (Zavala et al, 2008). Moreover, the AId innervates the nucleus accumbens (NA) core, a structure known to regulate cocaine seeking in rats, supporting a potential role for the AId in cocaine-seeking behavior (McFarland et al, 2003; Voorn et al, 2004). Indeed, previous work found that AId inactivation reduces cocaine seeking during a reinstatement test in which a contextual odor stimulus associated with cocaine was presented with a conditioned light cue (Di Pietro et al, 2006). In contrast, recent work found that lesions of the anterior portion of the IC, including the AId, potentiated cocaine-seeking behaviors when rats underwent forced abstinence and were then reintroduced to the cocaine-seeking context (Pelloux et al, 2013), leaving the role of the IC in the reinstatement of cocaine seeking unclear.It has been argued that the IC regulates relapse to drug use owing to its role in mediating interoceptive cues (Naqvi et al, 2014). A potential key mediator of these interoceptive cues within the IC is corticotropin-releasing factor (CRF; Naqvi and Bechara, 2009), which is expressed throughout the cortex and at relatively high levels in the IC (Sanchez et al, 1999; Van Pett et al, 2000). Indeed, evidence suggests that the central CRF system has a critical role in driving drug addiction and relapse (Koob, 2013; Zorrilla et al, 2014). Nonetheless, despite the potential significance of this issue, the role of the IC, including its different subregions and CRF1 (CRF receptor-1) receptors, has not been extensively examined in the reinstatement of cocaine-seeking behavior. Therefore, the present study investigated whether these two subregions of the IC, the AId and PIc, regulate cue-induced reinstatement, as well as whether blocking CRF1 receptors in the AId influences cocaine-seeking behavior during reinstatement.     

Screening and Management of Delirium in Critically Ill Patients

Delirium is highly prevalent in the critically ill population and has been associated with numerous negative outcomes including increased mortality. The presentation of a delirious patient in the intensive care unit (ICU) is characterized by a fluctuating cognitive status and inattention that varies dramatically among patients. Delirium can present in 3 different motoric subtypes: hyperactive, hypoactive, and mixed. Two tools, the Intensive Care Delirium Screening Checklist and Confusion Assessment ICU, are validated and recommended for the detection of delirium in critically ill patients. The identification of delirium in a critically ill patient should be facilitated using one of these tools. An intermediate form of delirium known as subsyndromal delirium also exists, although the significance of this syndrome is largely unknown. Another phenomenon known as sedation-related delirium has been recently described, although more research is needed to understand its significance. Patients in the ICU are exposed to many risk factors for developing delirium; controlling these risk factors is essential for preventing delirium development in critically ill patients. Nonpharmacologic interventions have been shown to prevent patients from developing delirium. Prevention is crucial because once delirium develops pharmacologic therapy is limited.Delirium is highly prevalent in critically ill patients and has been reported to occur in over 80% of mechanically ventilated patients.^1–3 A host of negative outcomes have been associated with delirium including increased intensive care unit (ICU) mortality, increased inpatient mortality, increased ICU length of stay, increased inpatient length of stay, and long-term cognitive impairment.^2,4–8 Unfortunately, the pathophysiology of this syndrome is not well understood. Proposed mechanisms for pathogenesis include neuroinflammation and neurotransmitter imbalances.⁹ The limited knowledge of delirium pathogenesis contributes to the difficulties encountered in managing this common, burdensome syndrome.     

Retrospective Review of Critically Ill Patients Experiencing Alcohol Withdrawal: Dexmedetomidine Versus Propofol and/or Lorazepam Continuous Infusions

Background:

Alcohol withdrawal symptoms can be difficult to manage and may lead to an intensive care unit (ICU) admission. Patients experiencing severe alcohol withdrawal often require high doses of sedatives, which can lead to respiratory depression and the need for endotracheal intubation. Dexmedetomidine, an alpha-2 adrenoreceptor agonist, provides adequate sedation with little effect on respiratory function when compared to other sedatives.

Objective:

To evaluate sedation with a continuous infusion of dexmedetomidine versus propofol and/or lorazepam in critically ill patients experiencing alcohol withdrawal.

Methods:

A retrospective chart review was conducted on ICU admissions between March 2002 and April 2009 for alcohol withdrawal patients who necessitated treatment with a continuous infusion of dexmedetomidine, propofol, and/or lorazepam. Primary outcomes included the incidence of mechanical ventilation, length of mechanical ventilation (if applicable), and ICU and hospital length of stay.

Results:

Fifteen patients were treated with a continuous infusion of dexmedetomidine, and 17 were treated with an infusion of propofol and/or lorazepam. Two patients (13.3%) required intubation and mechanical ventilation in the dexmedetomidine group versus 10 (58.8%) in the propofol and/or lorazepam group (P = .006). Length of stay in the ICU was 53 hours for patients treated with dexmedetomidine versus 114.9 hours in the propofol and/or lorazepam group (P = .016). Hospital length of stay was less for the dexmedetomidine group, 135.8 hours versus 241.1 hours in the propofol and/or lorazepam group (P = .008).

Conclusions:

Dexmedetomidine use was associated with a decrease in the incidence of endotracheal intubation when used to sedate patients experiencing alcohol withdrawal. Patients transferred to a lower level of care faster and were discharged from the hospital sooner when treated with dexmedetomidine.Key Words: alcohol, dexmedetomidine, lorazepam, propofol, withdrawalThere are approximately 18.3 million people in the United States dependent on or abusing alcohol and 2.9 million people requiring treatment for problems related to alcohol use.¹ The impact of alcohol withdrawal syndrome can be devastating, both physically and neurologically. The syndrome can include headache, anxiety, hallucinations, nausea and vomiting, sweating, seizures, irritability, and the most severe form of alcohol withdrawal, delirium tremens. Patients experiencing delirium tremens have a mortality rate of up to 5%.² The American Society of Addiction Medicine guidelines for the management of alcohol withdrawal delirium recommend sedative-hypnotic drugs, such as benzodiazepines, as the primary agents for managing alcohol withdrawal syndrome.³The goal of alcohol withdrawal treatment is to relieve the patients’ agitation and prevent the further development of more severe symptoms. Some patients may experience symptoms such as increased levels of anxiety, hallucinations, and delirium tremens. In these severe cases, escalating benzodiazepine doses (to include initiation of a continuous infusion) or initiation of another sedative, such as propofol or phenobarbital, becomes necessary to control agitation. The use of sedatives can cause a decrease in respiratory drive, which can lead to patients requiring transfer to a higher level of care with the potential for intubation and mechanical ventilator support.At North Colorado Medical Center (NCMC), patients undergoing alcohol withdrawal are initially treated with benzodiazepines. If escalating doses of benzodiazepines are unable to control agitation and other alcohol withdrawal symptoms, patients are evaluated by the physician for transfer to the intensive care unit (ICU). In the past, the standard of care in the NCMC ICU for patients experiencing severe alcohol withdrawal not controlled by intermittent benzodiazepines was the initiation of a benzodiazepine and/or propofol infusion based on the physician’s assessment and preference. Often these patients required intubation and mechanical ventilation. Recently, however, the sedation of patients experiencing severe alcohol withdrawal is increasingly being managed with dexmedetomidine in the ICU at NCMC.Clonidine has historically been used for treatment and prophylaxis of the symptoms of alcohol withdrawal.^3–9 Dexmedetomidine is a centrally acting, relatively selective, alpha2-adrenergic agonist similar to clonidine with sedative and analgesic properties. Dexmedetomidine reduces the stress response, decreases norepinephrine and epinephrine levels, and attenuates increases in heart rate and blood pressure without depressing the respiratory drive.^10,11The use of dexmedetomidine has been noted in multiple case reports, case series, and one small randomized controlled trial as a possibly effective agent for the management of alcohol withdrawal.^12–19 The case reports and case series primarily reported on safety, reduced benzodiazepine doses, and reduced delirium scores in the use of dexmedetomidine in alcohol withdrawal patients. The one randomized, blinded, placebo-controlled trial published to date by Mueller et al compared dexmedetomidine to placebo in patients with severe alcohol withdrawal. The primary endpoint was benzodiazepine requirements in the first 24 hours and cumulative dose over the first 7 days of hospitalization. They reported a reduced 24-hour benzodiazepine dose in the dexmedetomidine group and no difference in the 7-day cumulative dose between groups.¹²One of the main advantages of dexmedetomidine is that it does not cause respiratory depression.¹¹ This is especially important in patients admitted to the ICU for severe alcohol withdrawal. Studies have demonstrated that patients admitted to the ICU with severe alcohol withdrawal have a high rate of intubation, reportedly 22% to 65%.²⁰ Ventilator-associated pneumonia (VAP) can occur in 10% to 20% of patients receiving greater than 48 hours of mechanical ventilation. Patients who contract VAP have increased hospital costs of more than $10,000 per day, increased ICU length of stay by 5 to 7 days, and, in some reports, increased mortality.²¹ Furthermore, intubation and mechanical ventilation on ICU day 1 has been recognized as a predictor of a longer length of hospital stay.²²Assessment and documentation of the effectiveness of dexmedetomidine for treatment of alcohol withdrawal, while growing rapidly, is still lacking in the medical literature. The purpose of this retrospective observational study was to evaluate the incidence and duration of mechanical ventilation and the length of ICU and hospital stay in alcohol withdrawal patients treated with dexmedetomidine, propofol, and/or lorazepam continuous infusions.     

Lipidomics Revealed Idiopathic Pulmonary Fibrosis-Induced Hepatic Lipid Disorders Corrected with Treatment of Baicalin in a Murine Model

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease. The current standard treatment with glucocorticoids (GCs) leads to many adverse effects, and its effectiveness is questionable. Thus, it is critical and urgent to find new drug(s) for treatment of IPF. Baicalin (BAI) is an attractive candidate for this purpose. Herein, utilizing shotgun lipidomics, we revealed that IPF could lead to a lipid disorder of the liver in an animal model induced by bleomycin and confirmed through histopathological studies of the lung. Lipidomics further demonstrated that this disorder could virtually be corrected after treatment with BAI, but not with dexamethasone (DEX) (a commonly used GC for treatment of IPF). In contrast, the treatment with DEX did not improve IPF but led to tremendous alterations in hepatic lipidomes and accumulation of fat in the liver, which was very different from the lipid disorder induced by IPF. The underpinning mechanisms of the IPF-resultant lipid disorder and DEX-induced lipotoxicity as revealed by shotgun lipidomics were extensively discussed. Taken together, the current study showed that IPF could lead to hepatic lipid disorder, which can be treated with BAI, and demonstrated that lipidomics could be a powerful tool for drug screening.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9714-4) contains supplementary material, which is available to authorized users.KEY WORDS: baicalin, hepatic lipidome, idiopathic pulmonary fibrosis, multidimensional mass spectrometry, shotgun lipidomicsIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and ultimately fatal lung disease of unknown etiology. It usually occurs between 50 and 70 years of age and is characterized by the histological pattern of usual interstitial pneumonia (1,2). The onset of its symptoms is gradual, beginning with nonproductive cough, minor signs of inflammation, and exertional dyspnea. However, it almost always causes rapid fibrotic destruction of the lung, and the survival time from the onset of symptoms ranges from 4 to 5 years (3,4).Bleomycin (BLM) is a chemotherapeutic antibiotic used for treatment of some types of carcinomas but exhibits a dose-dependent pulmonary toxicity in most patients (5). Intratracheal instillation of BLM into the lungs of animal species results in symptoms and lung damage that essentially resemble human IPF, both histologically and physiologically. Thus, BLM has been widely utilized in animal models to cause injury and fibrotic lesions in the lung interstitium (6–10). In contrast, inhibition of lung inflammation and lipid peroxidation has been employed as therapeutic strategies for IPF (11–13).So far, there is no cure or even effective treatment for IPF. In clinic, oral glucocorticoids (GCs) have been used as the standard treatment of IPF for a long time (4). Dexamethasone (DEX) is a synthetic member of GC and is commonly used in the treatment of IPF. DEX treatment may lead to symptomatic relief, but it appears neither to halt the progression of fibrosis nor to improve life expectancy (14). Moreover, high-dosage and/or long-term treatment with DEX leads to severe adverse effects, including hepatic injury (15,16). Adverse hepatic effects (e.g., hepatic steatosis (17), hepatic insulin resistance (15), and activation of GC receptors (16)) are very common, because the liver plays a key role in the control of glucose and lipid homeostasis and DEX is metabolized primarily in the liver (18). DEX treatment elevates fatty acid synthesis (19,20) and causes triacylglycerol (TAG) accumulation in the liver, which contributes to hepatic insulin resistance and pathophysiology of metabolic syndrome (21). Furthermore, liver disease is one of the major problems in IPF due to oxygen deficiency. Accordingly, it is critical and urgent to discover new drug(s) for treatment of IPF. Recently, the application of baicalin (BAI), a flavonoid compound, for treatment of IPF has been given great attention (22). It has been reported that BAI possesses the anti-inflammatory, anti-oxidative, and anti-tumor functions, while also scavenging free radicals (23–26). However, there is little information regarding the effects of BAI on IPF-induced hepatic lipid changes.Herein, we reported a lipidomics study by using multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) (27–29) on evaluating the effects of BAI on hepatic lipidomes of a mouse model of IPF that was induced by BLM and validated through the histopathological examination of lung tissues. To our great surprise, shotgun lipidomics revealed a significant lipid disorder in the liver of the IPF animal model. Treatment of IPF animals with BAI not only cured the lung complication, but also virtually corrected all the hepatic lipid disorder. In contrast to the BAI treatment, treatment of the model with DEX resulted in remarkable alterations in different lipid classes and molecular species and severe accumulation of TAG amount. Moreover, lipidomics studies also allowed us to uncover the biochemical mechanisms responsible for the altered hepatic lipidomes of the IPF model and following its treatments.     

Keynote Lectures (L)

There is very often a great gap between the performance of oral drug delivery systems in vitro and in vivo. During the last decade modern high resolution and/or real time imaging techniques like Magnetic Marker Monitoring (MMM) [1] or Magnetic Resonance Imaging (MRI) [2, 3] have provided new insights into the in vivo performance of drug delivery systems and their interaction with the physiology of the gastrointestinal tract. The physiological conditions for drug absorption along the gastrointestinal tract are far from being constant. This applies to the expression of transport proteins and metabolizing enzymes as well as for the luminal conditions [3, 4]. Accordingly, gastrointestinal passage of a drug delivery system plays a crucial role for drug absorption. Gastrointestinal transit is also not a constant process. It is strongly controlled by feedback mechanisms that involve neuronal and hormonal signal pathways. In contrast to widespread assumption, transit times through all gastrointestinal organs, i. e. stomach, small intestine and colon, are highly variable. Gastric residence times are in general dependent on the energy content of the gastric filling. The rate of gastric emptying under fed conditions is controlled by the energy content of the meal, the energy requirement of the body and feedback mechanisms like the ileal brake mechanism. Furthermore, the rate of gastric emptying under fed conditions is also influenced by particle size. As a consequence, the emptying of drug substances from the digesting stomach is dependent on three main factors, the gastric emptying rate of the meal, the intragastric distribution of the drug and the particle size of the formulation. Examples for the in vivo behavior of different oral controlled release systems and resulting drug plasma concentration profiles will be shown and discussed.     

Social Stress and Psychosis Risk: Common Neurochemical Substrates?

Environmental risk factors have been implicated in the etiology of psychotic disorders, with growing evidence showing the adverse effects of migration, social marginalization, urbanicity, childhood trauma, social defeat, and other adverse experiences on mental health in vulnerable populations. Collectively, social stress may be one mechanism that could link these environmental risk factors. The exact mechanism(s) by which social stress can affect brain function, and in particular the molecular targets involved in psychosis (such as the dopaminergic (DA) system), is (are) not fully understood. In this review, we will discuss the interplay between social environmental risk factors and molecular changes in the human brain; in particular, we will highlight the impact of social stress on three specific neurochemical systems: DA, neuroinflammation/immune, and endocannabinoid (eCB) signaling. We have chosen the latter two molecular pathways based on emerging evidence linking schizophrenia to altered neuroinflammatory processes and cannabis use. We further identify key developmental periods in which social stress interacts with these pathways, suggesting window(s) of opportunities for novel interventions. Taken together, we suggest that they may have a key role in the pathogenesis and disease progression, possibly provide novel treatment options for schizophrenia, and perhaps even prevent it.Psychosis is characterized by a constellation of symptoms that includes abnormal perceptions and beliefs, usually called positive symptoms. Negative symptoms (eg, anhedonia, social withdrawal, etc) and cognitive deficits (eg, impaired memory, attention, executive functions, etc) are also evident, and represent major predictors of functional outcome. Epidemiological data have consistently demonstrated a well-replicated association between early environmental social risk factors and psychosis. The exact mechanism(s) by which social stress can affect brain function, and in particular the molecular targets involved in psychosis (such as the dopaminergic (DA) system), are not fully understood. In this review, we will discuss the interplay between social environmental risk factors and molecular changes in the human brain; in particular, we will highlight the impact of social stress on three specific neurochemical systems: DA, neuroinflammation/immune, and endocannabinoid (eCB) signaling. We have chosen the latter two molecular pathways based on emerging evidence linking schizophrenia to altered neuroinflammatory processes (Carter et al, 2014) and cannabis use (Andreasson et al, 1987; Arseneault et al, 2002; Harley et al, 2010; Leweke et al, 2007; Morgan et al, 2013). Although a number of other neurochemical systems have been implicated in schizophrenia, such as the glutamate system (Carter et al, 2014; Coyle, 2012; Javitt, 2012), the scope of this review is limited to the molecular systems with existing human data on the effects of psychosocial stress, notwithstanding encouraging findings regarding stress-induced glutamate alterations obtained in animal studies (Gan et al, 2014; Jiang et al, 2013). In this article, stress is broadly defined as either cortisol alterations or social manipulations, which are appraised to exceed the adaptive capacity to cope.