Handbook of experimental pharmacology
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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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Handb Exp Pharmacol · Jan 2008
Review Historical ArticleInhalation anaesthesia: from diethyl ether to xenon.
Modern anaesthesia is said to have began with the successful demonstration of ether anaesthesia by William Morton in October 1846, even though anaesthesia with nitrous oxide had been used in dentistry 2 years before. Anaesthesia with ether, nitrous oxide and chloroform (introduced in 1847) rapidly became commonplace for surgery. Of these, only nitrous oxide remains in use today. ⋯ Recently there has been a renewed interest in xenon, one of the noble gases. Xenon has many of the properties of an ideal anaesthetic. The major factor limiting its more widespread is the high cost, about 2,000 times the cost of nitrous oxide.
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Handb Exp Pharmacol · Jan 2008
ReviewInhibitory ligand-gated ion channels as substrates for general anesthetic actions.
General anesthetics have been in clinical use for more than 160 years. Nevertheless, their mechanism of action is still only poorly understood. In this review, we describe studies suggesting that inhibitory ligand-gated ion channels are potential targets for general anesthetics in vitro and describe how the involvement of y-aminobutyric acid (GABA)(A) receptor subtypes in anesthetic actions could be demonstrated by genetic studies in vivo.
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The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. ⋯ In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.
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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.