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Current pharmaceutical design [journal]
- Alert cell strategy: mechanisms of inflammatory response and organ protection. [Journal Article]
- Curr Pharm Des 2014; 20(36):5766-78.
Systemic inflammatory response syndrome (SIRS) is triggered by various factors such as surgical operation, trauma, burn injury, ischemia, pancreatitis and bacterial translocation. Sepsis is a SIRS associated with bacterial infection. SIRS and sepsis tend to trigger excessive production of inflammatory cytokines and other inflammatory molecules and induce multiple organ failure, such as acute lung injury, acute kidney injury and inflammatory cardiac injury. Epithelial and endothelial cells in some major organs express inflammatory receptors on the plasma membrane and work as alert cells for inflammation, and regulation of these alert cells could have a relieving effect on the inflammatory response. In inflammatory conditions, initial cardiac dysfunction is mediated by decreased preload and adequate infusion therapy is required. Tachyarrhythmia is a complication of inflammatory conditions and early control of the inflammatory reaction would prevent the structural remodeling that is resistant to therapies. Furthermore, there seems to be crosstalk between major organs with a central focus on the kidneys in inflammatory conditions. As an alert cell strategy, volatile anesthetics, sevoflurane and isoflurane, seem to have anti-inflammatory effects, and both experimental and clinical studies have shown the beneficial effects of these drugs in various settings of inflammatory conditions. On the other hand, in terms of intravenous anesthetics, propofol and ketamine, their current status is still controversial as there is a lack of confirmatory evidence on whether they have an organ-protective effect in inflammatory conditions. The local anesthetic lidocaine suppressed inflammatory responses upon both systemic and local administration. For the control of inflammatory conditions, anesthetic agents may be a target of drug development in accordance with other treatments and drugs.
- Editorial: novel insights into the role of anesthetics and opioids in organ or tissue protection. [Journal Article]
- Curr Pharm Des 2014; 20(36):5671-2.
Evidence is accumulating that anesthetics as well as opioids demonstrate some protective effects toward several organs including the heart and brain. However, in the field of anesthesiology, a wide range of reviews regarding such topics is scarce. Therefore, it has been difficult for clinicians as well as scientists to obtain crucial information about anesthetics and opioids from one issue of a journal. In this context, a series of reviews covering protective effects of anesthetics and opioids from both basic and clinical aspects were conducted in this issue of the Current Pharmaceutical Design "Novel insights into the role of anesthetics and opioids in organ or tissue protection." Kitahata et al.  discussed the role of mitochondria in anesthetic pre- and post-conditioning based on the results from basic experiments. During pre-conditioning, low levels of reactive oxygen species, which are produced by anesthetics in the mitochondria, act as a trigger to prevent cardiomyocyte death. During post-conditioning, decreased mitochondrial matrix pH, which was caused by anesthetics, triggers the onset of a rapid protective effect. The mitochondrial membranes have several ion channels that act as major determinants of cellular life and death under pathophysiological conditions. Mitochondrial permeability transition pores are end effectors, which contribute to myocardial preand post-conditioning. Mitochondria have been shown to play a role in the myocardial protective mechanisms by anesthetics, and they are both triggers and targets of cardioprotection in response to ischemia/reperfusion injury. Roth et al.  outlined a general overview of caveolae and caveolins and their role in protective signaling with a focus on the effects of volatile anesthetics. Caveolae are flask-like invaginations of the cell surface that have been identified as signaling epicenters. Within these microdomains, caveolins are structural proteins of caveolae, which are able to interact with numerous signaling molecules affecting temporal and spatial dimensions required in cardiac protection. This complex moiety is essential to the mechanisms of organ protection related to volatile anesthetics. Bonney et al.  focused on adenosine signaling in the context of anesthetic cardioprotection where they highlight new discoveries that could lead to new therapeutic concepts to treat myocardial ischemia using anesthetic pre-conditioning. Although the mechanism through which anesthetics can mimic ischemic pre- or post-conditioning is still unknown, adenosine generation and signaling are the most redundant triggers in ischemic pre- and post-conditioning. In fact, adenosine signaling has been implicated in isoflurane-mediated cardioprotection. Cardioprotection has been associated with all subtypes of adenosine receptors, although the role of each remains controversial. Recently, more specific receptor agonists and new genetic animal models have become available to pave way towards new discoveries. As such, the adenosine A2b receptor was shown to be one of the adenosine receptors whose cardiac expression is induced by ischemia in both mice and humans and whose function is implicated in ischemic pre- and post-conditioning. Riess et al.  provided an overview of mechanisms of opioid-induced protection against myocardial ischemia/reperfusion injury, as observed in cells, tissues and whole organs and in different species including humans, and provide an outlook on future directions and drug development. - and/or -opioid receptor activation is involved in direct myocardial protection, while the role of -opioid receptors seems less clear. In addition, differential affinities to the three opioid-receptor subtypes by various agonists and cross-talk among different G-protein coupled receptors render conclusions regarding opioid-mediated cardioprotection challenging. Zaugg et al.  showed growing evidence that volatile anesthetics and opioids provide cardioprotection in cardiac and noncardiac surgical patients. However, it is crucial to note that age, diabetes and myocardial remodeling diminish the cardioprotective benefits of these agents. They also emphasized that in patients at risk for perioperative cardiovascular complications, it is not recommended to use "anti-conditioning" drugs, including sulfonylureas and cyclooxygenase-2 inhibitors, and to avoid interference in cardioprotection between sevoflurane and propofol. Kawahito et al.  described the physiological and pathological roles of ATP-sensitive K+ channels in vascular smooth muscle and the effects of anesthetics toward these channels. Metabolic stresses including ischemia, hypoxia, hypercapnea and acidosis activate these channels, resulting in maintenance of the blood flow in vital organs including the heart and brain. Volatile anesthetics mostly enhance vasodilator effects mediated by these channels, whereas intravenous and local anesthetics reduce them. Although accumulated experimental evidence suggests that many anesthetics can modify the K+ channel function, further studies in clinical settings are certainly needed to improve the anesthetic management. Ishikawa et al.  described basic concepts of pathology following spinal cord injury and how anesthetics contribute to spinal protection. They mentioned possible neuroprotection mediated by anesthetics and/or analgesics in the perioperative period. In this regard, Ishikawa et al. recommend employing isoflurane but not barbiturates for this particular purpose. They also introduced recent advances of understanding stem cell biology, which may lead us to successful recovery of spinal cord function after the insult. Kakinohana  described that some anesthetics, especially inhalational anesthetics, may clinically provide neuroprotective effects against the spinal cord ischemia, but the administration of neuraxial opioid after spinal cord ischemia might exacerbate neurological dysfunction. Indeed, isoflurane as well as sevoflurane probably provides neuroprotective effects against spinal ischemia via activation of TWIK-related K channels- 1 or the ATP sensitive K+ channels. In addition, nitric oxide inhalation might be a tool to protect the spinal cord from intraoperative ischemia in patients undergoing aortic cross-clamp during surgery. In contrast, clinical cases and experimental studies have indicated that neuraxial opioids are capable of exacerbating neurological deficits even after a non-injurious interval of spinal ischemia. Ishida et al.  examined the history of anesthetic neuroprotection research, and then systematically reviewed major clinical trials of anesthetic neuroprotection. They found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. As a result, they concluded that anesthetics appear not to have efficacy for neuroprotection in humans. They state that the quality of science conducted to date can be markedly improved upon to allow more rational clinical trial design and better opportunity to provide a convincing answer to this question. Hatakeyama et al. , showed that organ injury accompanied by an inflammatory condition including systemic inflammatory response syndrome and sepsis mainly involves activation of nuclear factor-B at an early stage and activator protein-1 at an advanced stage. They emphasized that the pathological condition induces apoptosis and cell death via the inflammatory activation of alert cells. Volatile and local anesthetics seem to have anti-inflammatory effects, and both experimental and clinical studies have shown the beneficial effects of these drugs in various settings of inflammatory conditions. In contrast, intravenous anesthetics lack confirmatory evidence that they are organ-protective in Azma et al.  documented clinical evidence indicating beneficial roles of neuraxial anesthesia/analgesia in the prevention of venous thromboembolism in surgical patients. Clinical as well as experimental findings point to the involvement of immune cells in red thrombus generation and to the interaction of anesthetics with these cells. Of these, the adhesion molecule associated with the formation of monocyte platelet aggregation as well as the substance P-neurokinin-1 receptor pathway should be emphasized. Local anesthetics and neurokinin-1 receptor antagonists may possess prevention of venous thrombotic disorders in perioperative settings. Ishii  summarized recent clinical trials on the effects of opioids on ischemic heart disease and discussed the barriers to the use of opioids for cardioprotection. In vitro and in vivo studies have demonstrated that the opioid system plays an important role in maintaining cardiac function. In support of these research findings, there is clinical evidence that opioids, especially acting on κ, σ μ3 opioid receptors, might be effective as cardioprotective drugs. Although opioids are administered to many patients undergoing surgery or management in the intensive care unit, no recommendations about their use for the preconditioning/management of myocardial ischemia have been included in recent clinical guidelines due to the weak clinical evidence about their effects. To establish reproducible cardioprotective opioid-based treatments, we must clarify the patient factors that influence the cardiac response to opioids. In summary, this issue contains a broad range of findings regarding protective effects of anesthetics and opioids, which are currently used in clinical anesthesia, on a variety of organs and tissues including those in some pathological conditions. However, many questions remain, and will have to be further examined to improve the quality of clinical anesthesia.
- Clinical Applications of Choline PET/CT in Brain Tumors. [JOURNAL ARTICLE]
- Curr Pharm Des 2014 Sep 15.
Malignant gliomas and metastatic tumors are the most common forms of brain tumors. From a clinical persepctive, neuroimaging plays a significant role, in diagnosis, treatment planning, and follow-up. To date MRI is considered the current clinical gold standard for imaging, however, despite providing superior structural detail it features poor specificity in identifying viable tumors in brain treated with surgery, radiation, or chemotherapy. In the last years functional neuroimaging has become largely widespread thanks to the use of molecular tracers employed in cellular metabolism which has significantly improved the management of patients with brain tumors, especially in the post-treatment phase. Despite the considerable progress of molecular imaging in oncology its use in the diagnosis of brain tumors is still limited by a few well-known technical problems. Because 18F-FDG, the most common radiotracer used in oncology, is avidly accumulated by normal cortex, the low tumor/background signal ratio makes it difficult to distinguish the tumor from normal surrounding tissues. By contrast, radiotracers with higher specificity for the tumor are labeled with a short half-life isotopes which restricts their use to those centers equipped with a cyclotron and radiopharmacy facility. 11C-Choline has been reported as a suitable tracer for neuroimaging application. The recent availability of choline labeled with a long half-life radioisotope as 18F increases the possibility of studying this tracer's potential role in the staging of brain tumors. The present review focuses on the possible clinical applications of PET/CT with choline tracers in malignant brain tumors and brain metastases, with a special focus on malignant gliomas.
- The Case for Using Higher Doses of First Line Anti-Tuberculosis Drugs to Optimize Efficacy. [JOURNAL ARTICLE]
- Curr Pharm Des 2014 Sep 1.
Apart from new anti-tuberculosis drug development, another approach for tuberculosis (TB) treatment optimization is to derive maximum benefit of current agents. However, the dosage of current anti-TB drug regimens has never been optimized according to the exposure-effect relationships of each drug. The objective of this article is to review the latest pharmacokinetic, pharmacodynamic, experimental, and clinical data concerning the use of higher doses of first-line anti-TB drugs to improve the efficacy of pulmonary tuberculosis treatment. Exposure-effect relationships have been described for all first-line anti-TB agents. There is convincing evidence that patients would benefit from higher rifamycin exposure. This could be achieved by using higher daily doses of rifampin, or more frequent dosing of rifapentine. The dose-dependent activity of pyrazinamide observed in hollow-fiber and animal models suggests that higher doses of pyrazimamide might be more efficacious, but the tolerability of such higher doses needs to be investigated in humans. It is likely that higher doses of ethambutol would be associated with higher antibacterial effect, but the dose-related ocular toxicity of the drug precludes such practice. For isoniazid, dose individualization is required to optimize patient care. The use of higher than standard doses of isoniazid in fast acetylators should result in greater early bactericidal activity. To conclude, the use of higher doses for some of first-line anti-TB agents has definite potential for shortening or improving TB treatment.
- Mycobacterium w Immunotherapy for Treating Pulmonary Tuberculosis - a Systematic Review. [JOURNAL ARTICLE]
- Curr Pharm Des 2014 Sep 5.
To evaluate Mycobacterium w (M w) immunotherapy as an adjunct to chemotherapy in participants with pulmonary TB (PTB). Search strategy: In January 2012, we performed both a database search, a handsearch and corresponded with experts in the field. Selection criteria: Randomised and quasi-randomised controlled trials of M w immunotherapy versus placebo (or no control) for participants with PTB. Data collection and analysis: Two of the authors (SP and ZK) independently extracted data. Dichotomous outcomes were analysed using risk ratios (RR) and 95% confidence intervals (CI). Outcomes: The primary outcome was to determine the effect of M w therapy on sputum conversion. Secondary outcomes were to determine the frequency of adverse reactions. Main Results: Three trials (four papers) involving 368 participants were included. All four papers had methodological flaws. Overall, 173 participants received M w and 168 participants received placebo or no control. M w immunotherapy was effective at reducing time to sputum conversion at days 15 (RR 2.31; 95% CI 1.75 to 3.06; P < 0.001) and 30 (RR 1.83; 95% CI 1.12 to 2.98; P = 0.02). After day 30, benefit was only demonstrated in the category II TB (re-treatment). Conclusions: The meta-analysis suggests benefit as regards the time to sputum conversion. The available data on M w immunotherapy for participants with PTB are however methodologically flawed. We advise that M w be investigated in a well-structured, randomized controlled trial.
- Molecular Mechanisms Involved in the Control of Neurohypophyseal Hormones Secretion. [JOURNAL ARTICLE]
- Curr Pharm Des 2014 Sep 5.
The regulation of neurohypophyseal peptides secretion reflects the convergence of a large number of afferent neural pathways on vasopressinergic and oxytocinergic neurons of supraoptic (SON) and paraventricular nuclei (PVN). In addition to afferent input, vasopressin and oxytocin can also exert an autocrine regulation of neuronal activity. In fact, magnocellular neurons (MCNs) of SON and PVN are able to secrete these hormones not only at the endings of their terminal axons, but also from their dendrites and this local release, by activating a range of ion gated, ion channel and G protein coupled receptors, participate in pre- and post-synaptic modulation of neural activity of MCNs. In this review we analyzed the molecular mechanisms involved in the control of neurohypophyseal hormones secretion and related possible pharmacological targets.
- Bacteriophages and their Enzymes in Biofilm Control. [JOURNAL ARTICLE]
- Curr Pharm Des 2014 Sep 5.
Although free-swimming planktonic bacteria historically have been the typical focus of microbiological studies, the natural state of many or most bacteria is one where they instead are associated either with surfaces and/or each other. For many pathogenic as well as nuisance bacteria, including biofouling bacteria, it consequently is within the context of this biofilm state that antibacterial strategies must be implemented. For reasons that are not fully understood, however, biofilm-associated bacteria tend to be less susceptible to treatments with standard chemical antibacterial agents than are planktonic bacteria, and this appears to be especially an issue with the use of less-harsh agents such as antibiotics. Within a variety of contexts the development of less- or selectively toxic antibacterial agents capable of clearing biofilms therefore would be welcome. In this review we consider the use of three categories of such agents as anti-biofilm antibacterials. These are lytic viruses of bacteria, that is, bacteriophages, effecting phage-mediated biocontrol of bacteria (a.k.a., phage therapy); purified phage-encoded enzymes that digest bacterial cell-wall material (endolysins or simply lysins); and a second category of phage-encoded enzymes that digest the extracellular polymeric substance (EPS) that are particularly notable components of bacterial biofilms (EPS depolymerases). These agents have been shown to reduce bacterial density of a diversity of biofilms and, in many cases, tend to be lacking in inherent toxicity against the tissues of animals. Here we consider these phage-based anti-biofilm strategies with emphasis on ecological aspects of their action and with particular consideration of EPS depolymerases.
- Nitric Oxide: a Key Mediator of Biofilm Dispersal with Applications in Infectious Diseases. [JOURNAL ARTICLE]
- Curr Pharm Des 2014 Sep 5.
Studies of the biofilm life cycle can identify novel targets and strategies for improving biofilm control measures. Of particular interest are dispersal events, where a subpopulation of cells is released from the biofilm community to search out and colonize new surfaces. Recently, the simple gas and ubiquitous biological signaling molecule nitric oxide (NO) was identified as a key mediator of biofilm dispersal conserved across microbial species. Here, we review the role and mechanisms of NO mediating dispersal in bacterial biofilms, and its potential for novel therapeutics. In contrast to previous attempts using high dose NO aimed at killing pathogens, the use of low, non-toxic NO signals (picomolar to nanomolar range) to disperse biofilms represents an innovative and highly favourable approach to improve infectious disease treatments. Further, several NO-based technologies have been developed that offer a versatile range of solutions to control biofilms, including: (i) NO-generating compounds with short or long half-lives and safe or inert residues, (ii) novel compounds for the targeted delivery of NO to infectious biofilms during systemic treatments, and (iii) novel NO-releasing materials and surface coatings for the prevention and dispersal of biofilms. Overall the use of low levels of NO exploiting its signaling properties to induce dispersal represents an unprecedented and promising strategy for the control of biofilms in clinical and industrial contexts.
- Quorum Sensing and Biofilms in the Pathogen, Streptococcus Pneumoniae. [JOURNAL ARTICLE]
- Curr Pharm Des 2014 Sep 5.
Bacteria are able to colonize and thrive in a variety of different environments as a biofilm, but only within the last half century new insights have been gained in this complex biosystem. Bacterial biofilms play a major role in human health by forming a defensive barrier against antibacterial chemical therapeutics and other potential pathogens, and in infectious disease when the bacteria invade normally sterile compartments. Quorum sensing is the signaling network for cell to cell communication and utilized by bacteria to regulate biofilms and other cellular processes. This review will describe recent advances in quorum sensing and biofilms. Initially, it will focus on Streptococcus pneumoniae biofilm regulation and the involvement of the ComABCDE pathway. As part of this review an original analysis of the genotypic and phenotypic variation of the signaling molecule, ComC and its cognate receptor ComD, firstly within the pneumococcal species and then within the genus Streptococcus will be presented. Additionally, a pathway similar to ComABCDE, the BlpABCSRH that regulates bacteriocin and immunity protein production that inhibit the growth of competing bacteria will be described. This review will then examine a third quorum sensing mechanism in the pneumococcus, the LuxS/AI-2, and present a novel gene and protein sequence comparative analysis that indicates its occurrence is more universal across bacterial genera compared with the Com pathway, with more sequence similarities between bacterial genera that are known to colonize the mucosal epithelium.
- Quorum Sensing Inhibitors as Anti-Biofilm Agents. [JOURNAL ARTICLE]
- Curr Pharm Des 2014 Sep 5.
Biofilms are microbial sessile communities characterized by cells that are attached to a substratum or interface or to each other, are embedded in a self-produced matrix of extracellular polymeric substances and exhibit an altered phenotype compared to planktonic cells. Biofilms are estimated to be associated with 80% of microbial infections and it is currently common knowledge that growth of micro-organisms in biofilms can enhance their resistance to antimicrobial agents. As a consequence antimicrobial therapy often fails to eradicate biofilms from the site of infection. For this reason, innovative anti-biofilm agents with novel targets and modes of action are needed. One alternative approach is targeting the bacterial communication system (quorum sensing, QS). QS is a process by which bacteria produce and detect signal molecules and thereby coordinate their behavior in a cell-density dependent manner. Three main QS systems can be distinguished: the acylhomoserine lactone (AHL) QS system in Gram-negative bacteria, the autoinducing peptide (AIP) QS system in Gram-positive bacteria and the autoinducer-2 (AI-2) QS system in both Gram-negative and -positive bacteria. Although much remains to be learned about the involvement of QS in biofilm formation, maintenance, and dispersal, QS inhibitors (QSI) have been proposed as promising antibiofilm agents. In this article we will give an overview of QS inhibitors which have been shown to play a role in biofilm formation and/or maturation.