Naunyn-Schmiedeberg's archives of pharmacology
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Naunyn Schmiedebergs Arch. Pharmacol. · Aug 2008
ReviewInhaled corticosteroids and long-acting beta-agonists in adult asthma: a winning combination in all?
In the recent years, considerable insight has been gained in to the optimal management of adult asthma. Most adult patients with asthma have mild intermittent and persistent disease, and it is acknowledged that many patients do not reach full control of all symptoms and signs of asthma. Those with mild persistent asthma are usually not well controlled without inhaled corticosteroids (ICS). ⋯ The duration of treatment before initiating this dose reduction has, however, not been fully established. One of the combinations available to treat asthma (budesonide and formoterol) has also been assessed as both maintenance and rescue therapy with a further reduction in the risk for a severe exacerbation. Clinical effectiveness in the real world now has to be established, since this approach likely improves compliance with regular maintenance therapy.
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Naunyn Schmiedebergs Arch. Pharmacol. · Aug 2008
ReviewEmbracing emerging paradigms of G protein-coupled receptor agonism and signaling to address airway smooth muscle pathobiology in asthma.
G protein-coupled receptors (GPCRs) regulate numerous airway cell functions, and signaling events transduced by GPCRs are important in both asthma pathogenesis and therapy. Indeed, most asthma therapies target GPCRs either directly or indirectly. ⋯ In this review, we discuss current concepts regarding constitutive GPCR activity and receptor agonism, functional selectivity, compartmentalized signaling, and GPCR desensitization. We further discuss the relevance of these ideas to asthma and asthma therapy, while emphasizing their potential application to the GPCR signaling in airway smooth muscle that regulates airway patency and thus disease severity.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
ReviewProthymosin alpha plays a key role in cell death mode-switch, a new concept for neuroprotective mechanisms in stroke.
After stroke or traumatic damages, both necrotic and apoptotic neuronal death cause a loss of functions including memory, sensory perception, and motor skills. From the fact that necrosis has a nature to expand, while apoptosis to cease the cell death cascade in the brain, it is considered that the promising target for the rapid treatment for stroke is the necrosis. In this study, I introduce the discovery of prothymosin alpha (ProTalpha), which inhibits neuronal necrosis, and propose its potentiality of clinical use for stroke. ⋯ However, we found that ProTalpha-induced apoptosis is completely inhibited by the concomitant treatment with neurotrophins, which are up-regulated by ischemic stress in the brain. Of most importance is the finding that the systemic injection of ProTalpha completely inhibits the brain damages, motor dysfunction and learning memory defect induced by cerebral ischemia-reperfusion stress. As ProTalpha almost entirely prevents the focal ischemia-induced motor dysfunction 4 h after the start of ischemia, this protein seems to have a promising potentiality for clinical use.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
ReviewAt the frontline of Alzheimer's disease treatment: gamma-secretase inhibitor/modulator mechanism.
Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (Abeta) contribute to the etiology of Alzheimer's disease. beta- and gamma-secretases, which are responsible for the generation of Abeta, are plausible molecular targets for Alzheimer's disease treatment. gamma-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain. This unusual enzyme is composed of a high molecular weight membrane protein complex containing presenilin, nicastrin, Aph-1 and Pen-2. ⋯ Thus, understanding the molecular mechanism whereby gamma-secretase recognizes and cleaves its substrate is a critical issue for the development of compounds that specifically regulate Abeta-generating gamma-secretase activity. This review focuses on the structure and function relationship of gamma-secretase complex and the mode of action of the gamma-secretase inhibitors.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
ReviewCandidate gene polymorphisms predicting individual sensitivity to opioids.
Significant interindividual differences in opioid sensitivity can hamper effective pain treatment and increase the risk for substance abuse. Elucidation of the genetic mechanisms involved in the interindividual differences in opioid sensitivity would help establish personalized pain management. ⋯ Such information should aid in developing and improving the methods of predicting interindividual differences in opioid sensitivity. In the near future, it will be possible to predict the appropriate kinds and doses of opioids for individuals by analyzing genetic variations contributing to opioid sensitivity.