Handbook of experimental pharmacology
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It is today generally accepted that anesthetics act by binding directly to sensitive target proteins. For certain intravenous anesthetics, such as propofol, barbiturates, and etomidate, the major target for anesthetic effect has been identified as the gamma-aminobutyric acid type A (GABA(A)) receptor, with particular subunits playing a crucial role. ⋯ For the less potent steroid anesthetic agents the picture is less clear, although a relatively small number of targets have been identified as being the most likely candidates. In this review, we summarize the most relevant clinical and experimental pharmacological properties of these intravenous anesthetics, the molecular targets mediating other endpoints of the anesthetic state in vivo, and the work that led to the identification of the GABA(A) receptor as the key target for etomidate and aminosteroids.
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The heart has a strong endogenous cardioprotection mechanism that can be triggered by short periods of ischaemia (like during angina) and protects the myocardium during a subsequent ischaemic event (like during a myocardial infarction). This important mechanism, called ischaemic pre-conditioning, has been extensively investigated, but the practical relevance of an intervention by inducing ischaemia is mainly limited to experimental situations. Research that is more recent has shown that many volatile anaesthetics can induce a similar cardioprotection mechanism, which would be clinically more relevant than inducing cardioprotection by ischaemia. ⋯ Since ischaemia-reperfusion of the heart routinely occurs in a variety of clinical situations such as during transplant surgery, coronary artery bypass grafting, valve repair or vascular surgery, anaesthetic-induced cardioprotection might be a promising option to protect the myocardium in clinical situations. Initial studies now confirm an effect on surrogate outcome parameters such as length of ICU or in-hospital stay or post-ischaemic troponin release. In this chapter, we will summarize our current understanding of the three mechanisms of anaesthetic cardioprotection exerted by inhalational anaesthetics.
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Handb Exp Pharmacol · Jan 2008
ReviewAdvanced technologies and devices for inhalational anesthetic drug dosing.
Technological advances in micromechanics, optical sensing, and computing have led to innovative and reliable concepts of precise dosing and sensing of modern volatile anesthetics. Mixing of saturated desflurane flow with fresh gas flow (FGF) requires differential pressure sensing between the two circuits for precise delivery. The medical gas xenon is administered most economically in a closed circuit breathing system. ⋯ Delivery of xenon is presented, followed by a discussion of direct injection of volatile anesthetics and of a device designed to conserve anesthetic drugs. Next, innovative sensing technologies are presented for reliable control and precise metering of the delivered volatile anesthetics. Finally, we discuss the technical challenges of automatic control in low-flow and closed circuit breathing systems in anesthesia.
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Handb Exp Pharmacol · Jan 2008
ReviewCytokine, chemokine, and co-stimulatory fusion proteins for the immunotherapy of solid tumors.
This chapter describes the generation of novel reagents for the treatment of cancer using fusion proteins constructed with natural ligands of the immune system. Immunotherapy is a powerful therapeutic modality that has not been fully harnessed for the treatment of cancer. We and others have hypothesized that if the proper immunoregulatory ligands can be targeted to the tumor, an effective immune response can be mounted to treat both established primary tumors and distant metastatic lesions. ⋯ When used alone, both forms of costimulatory fusion proteins were found to produce in a s dose-dependent manner, complete regression of murine solid tumors. Evidence is presented to show that Treg cells play an important role in suppressing antitumor immunity since the deletion of these cells, when used in combination with LEC or costimulatory fusion proteins, produced profound and effective treatment with sustained memory. It is hoped that these data will further the preclinical development of soluble Fc and antibody based fusion proteins fro the immunotherapy of cancer.
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We do not know how general anesthetics cause their desired effects. Contrary to what has been thought until relatively recently, the clinical state of anesthesia consists of multiple components that are mediated via interaction of the anesthetic drugs with different targets on the molecular-cellular, the network, and the structural-anatomical levels. The molecular targets by which some of these drugs induce the different components of "anesthesia" may be rather specific: discrete mutations of single amino acids in specific proteins profoundly affect the ability of certain anesthetics to achieve specific endpoints. ⋯ The CNS appears to be susceptible to anesthetic neurotoxicity primarily at the extremes of ages, possibly via different pathways: in the neonate, during the period of most intense synaptogenesis, anesthetics can induce excessive apoptosis; in the aging CNS subtle cognitive dysfunction can persist long after clearance of the drug, and processes reminiscent of neurodegenerative disorders may be accelerated (Eckenhoff et al. 2004). At all ages, anesthetics affect gene expression-regulating protein synthesis in poorly understood ways. While it seems reasonable to assume that the vast majority of our patients completely restore homeostasis after general anesthesia, it is also time to acknowledge that exposure to these drugs has more profound and longer lasting effects on the brain than heretofore imagined.