Current pharmaceutical biotechnology
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Curr Pharm Biotechnol · Feb 2011
Review Case ReportsLipid resuscitation: a life-saving antidote for local anesthetic toxicity.
Local anesthetic toxicity is a rare, but potentially lethal, complication of regional anesthesia that cannot be prevented by any single measure. It is associated with CNS excitation and can lead to refractory cardiac dysfunction and collapse. The development of lipid emulsion for the treatment of anesthetic-induced toxicity resulted from a set of observations during a study on the potent, lipophilic drug bupivacaine and its associated clinical risk of intransigent cardiac toxicity in otherwise healthy individuals. ⋯ The underlying mechanisms of lipid resuscitation may be a combination of a 'lipid sink' and metabolic effect. Lipid rescue has led to a reduction in fatalities associated with severe systemic toxicity, but continued research is necessary for a better mechanistic understanding. Increased physician awareness and education, as well as optimized treatment protocols, will significantly reduce the rate of morbidity and mortality from local anesthetic toxicity.
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Curr Pharm Biotechnol · Feb 2011
ReviewNetwork of WNT and other regulatory signaling cascades in pluripotent stem cells and cancer stem cells.
Canonical WNT signaling activation leads to transcriptional up-regulation of FGF ligand, Notch ligand, non-canonical WNT ligand, WNT antagonist, TGFβ antagonist, and MYC. Non-canonical WNT signals inhibit canonical WNT signaling by using MAP3K7-NLK signaling cascade. Hedgehog up-regulates Notch ligand, WNT antagonist, BMP antagonists, and MYCN. ⋯ Fine-tuning of WNT, FGF, Notch, TGFβ/BMP, and Hedgehog signaling network by using small-molecule compounds could open the door for regenerative medicine utilizing pluripotent stem cells without tumorigenic potential. Because FGF, Hedgehog, TGFβ, and non-canonical WNT signals synergistically induce EMT regulators, such as Snail (SNAI1), Slug (SNAI2), TWIST, and ZEB2 (SIP1), tumor-stromal interaction at the invasion front aids cancer stem cells to acquire more malignant phenotype. Cancer stem cells occur as mimetics of normal tissue stem cells based on germ-line variation, epigenetic change, and somatic mutation of stem-cell signaling components, and then acquire more malignant phenotype based on accumulation of additional epigenetic and genetic alterations, and tumor-stromal interaction at the invasion front.