Pharmacokinetic and Other Considerations for Drug Therapy During Targeted Temperature Management.

OBJECTIVE: To synthesize an emerging body of literature describing pharmacokinetic alterations and related pharmacodynamic implications affecting drugs commonly used in patients receiving targeted temperature management following cardiac arrest. DATA SOURCES: Peer-reviewed articles indexed in PubMed. STUDY SELECTION: A systematic search of the PubMed database for relevant preclinical studies and clinical and observational trials of physiologic changes and drug pharmacokinetic and pharmacodynamic alterations, especially during targeted temperature management/therapeutic hypothermia, but also from cardiac surgery and acute stroke hypothermia models. DATA EXTRACTION: Detailed review of information contained in published scientific work. DATA SYNTHESIS: Physiologic changes during targeted temperature management significantly alter both the pharmacokinetic and the pharmacodynamic parameters of medications. Current literature describes these alterations and provides practical considerations for management of medications. Medication selection should center on the pharmacokinetics and pharmacodynamics of agents in an attempt to ameliorate potential adverse effects. CONCLUSIONS: This review provides an overview of physiologic changes associated with targeted temperature management and practical considerations for the management of medications. Clinicians should understand and anticipate potential drug-therapy interactions of targeted temperature management and mitigate adverse outcomes by appropriate medication selection, dosing, and monitoring. We discuss complications of hypothermia including shivering, electrolyte abnormalities, hemodynamic changes, arrhythmias, and seizures. We review management of these complications as well as considerations for sedation, analgesia, anticoagulation, and prognostication. Approach to interpretation of the clinical significance of drug interactions during targeted temperature management therapy is also addressed.

Inhibition of cytokinesis and akt phosphorylation by chaetoglobosin K in ras-transformed epithelial cells.

PURPOSE: Chaetoglobosin K (ChK), a bioactive natural product previously shown to have anti-tumor promoting activity in glial cells and growth inhibitory effects in ras-transformed fibroblasts, inhibited anchorage-dependent and anchorage-independent growth in ras-transformed liver epithelial cells. The purpose of this study was to identify cellular targets of ChK that mediate its anti-tumor effects. METHODS: Anchorage-independent cell growth assays, using soft agar-coated dishes, and anchorage-dependent growth assays were performed on transformed WB- ras1 cells. Phase/contrast and fluorescent microscopy were used to visualize cell morphological changes and DAPI-stained nuclei. Analyses of p21 Ras membrane versus cytosolic forms, p44/42 mitogen-activated protein kinase (MAPK) phosphorylation, Akt kinase phosphorylation and connexin 43 phosphorylation were performed by Western blotting. Gap junction-mediated cellular communication was measured by fluorescent dye transfer. RESULTS: Treatment of WB- ras1 cells with a non-cytotoxic dose of ChK inhibited both anchorage-dependent and anchorage-independent growth. Inhibited cells were generally larger and less spindle-shaped in morphology than vehicle-treated cells, many of which were multinucleate. Removal of ChK induced cytokinesis and a return to predominantly single-nucleate cells, suggesting that ChK inhibits cytokinesis. The proportion of membrane-associated versus cytosolic forms of p21 Ras was unchanged by ChK treatment, suggesting that ChK does not act as a farnesylation inhibitor. ChK treatment decreased the level of phosphorylation of Akt kinase, a key signal transducer of the Phosphatidylinositol 3-kinase pathway. In contrast, ChK had no effect on phosphorylation of p44/42 MAPK, which mediates the MAPK/ERK Ras effector pathway. Phosphorylation of the gap junction protein, connexin 43, shown previously to increase following treatment with other anti-Ras compounds, was also not altered by ChK, which correlated with its lack of effect on gap junction-mediated cellular communication. CONCLUSIONS: Our results demonstrate that ChK inhibits Akt kinase phosphorylation and cytokinesis in ras-transformed cells, which likely contribute to its ability to inhibit tumorigenic growth.

Reversal of the transformed phenotype and inhibition of peptidylglycine alpha-monooxygenase in Ras-transformed cells by 4-phenyl-3-butenoic acid.

Recent studies have shown that the proliferation of some tumor cells is dependent on autocrine growth loops that require amidated autocrine growth factors. Peptidylglycine alpha-monooxygenase (PAM) is required for amidation of these growth factors and, therefore, this enzyme is an attractive target for anti-tumor compounds. 4-Phenyl-3-butenoic acid (PBA) is an irreversible turnover-dependent inhibitor of PAM in vitro and has been shown to decrease lung cancer cell proliferation by inhibiting the synthesis of amidated growth factors. We show here that PBA (0.1 mg/mL) inhibits the growth of Ras-transformed epithelial cells (WB-Ras) but has little effect on the proliferation of normal epithelial cells (WB-Neo). The methyl ester derivative of PBA (PBA-Me) at 10-fold lower concentration also exhibits a selective inhibition of Ras-transformed cell growth compared to normal epithelial cell growth. In addition, PBA produces a significant upregulation of gap junctional communication between WB-Ras cells following 2-5 day treatments, with a corresponding increase in the degree of connexin 43 phosphorylation and an increase in the number of connexin 43-containing plasma membrane gap junction plaques. Western blot analyses indicate no effect of PBA on the proportion of p21 Ras in the membrane versus cytosolic fractions or on p44/42 MAP kinase phosphorylation. Furthermore, the cell morphology of PBA-treated WB-Ras cells is altered, so as to more closely resemble that of non-transformed WB-Neo cells. PAM activity was assayed in both WB-Ras and WB-Neo cells, and we demonstrate that PBA at long treatment times (4 days) inhibits PAM activity in both cell types at concentrations that produce selective growth inhibition of WB-Ras cells. Shorter PBA treatment times (24 h), however, inhibit PAM activity in WB-Ras but not WB-Neo cells, an effect that was mimicked by PBA-Me. Taken together, these results clearly demonstrate that PBA returns Ras-transformed cells to a more normal phenotype, a finding consistent with the known increased dominance of the Ras signaling pathway in transformed epithelial cells.