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Siriraj-ir.si.mahidol.ac.thCancer Chemother Pharmacol (1996) 38: 81—87 Andrew G. Ellis · Nicholas A. CrinisLorraine K. Webster Inhibition of etoposide elimination in the isolated perfused rat liverby Cremophor EL and Tween 80 Received: 5 January 1995/Accepted: 25 August 1995 Abstract Cremophor EL, a surfactant used in the clini- tion was 0.8 mg/ml, which previous studies have shown cal formulation of cyclosporine and paclitaxel, will re- to be clinically relevant and close to the optimal level verse the multidrug resistance (MDR) phenotype in for MDR reversal in vitro (1.0 mg/ml). Cremophor may vitro. As other MDR modulators can alter the phar- be a clinically useful MDR modulator, but it may alter macokinetics of cytotoxic drugs, the aim of this study the pharmacokinetics of the cytotoxic drug.
was to examine the effect of Cremophor and anotherMDR-reversing surfactant, Tween 80, on the hepatic Key words Etoposide · Multidrug resistance · elimination and biliary excretion of etoposide. Using the isolated perfused rat-liver model with 80 ml recir-culating perfusate containing 20% red blood cells and4% bovine serum albumin, etoposide (1.6 mg) with and without Cremophor (800 or 80 mg) or Tween 80(80 mg) was given into the perfusate reservoir, and One of the major reasons for failure of cancer chemo- perfusate and bile samples were collected for 3 h.
therapy is the presence of intrinsic or acquired drug Etoposide was measured by high-performance liquid resistance in malignant cells. Although a number of chromatography (HPLC) and Cremophor was meas- different mechanisms of drug resistance have been ured using a bioassay. Both surfactants changed the described, one of the most widely studied is multidrug etoposide elimination profile from biphasic to mono- resistance (MDR). Cells that display the MDR pheno- phasic. High-dose Cremophor increased the AUC type are cross-resistant to a broad spectrum of struc- (from 334$23 to 1540$490 g min ml\, P(0.05) turally and functionally unrelated drugs, including and decreased the total clearance (from 4.8$0.3 to epipodophyllotoxins, vinca alkaloids, paclitaxel, and 1.1$0.3 ml/min, P(0.05) and biliary clearance anthracyclines. Classic MDR is characterized by re- (from 2.6$1.1 to 0.5$0.2 ml/min, P(0.05) but de- duced intracellular accumulation of the cytotoxic drug creased the elimination half-life (from 62$17 to due to overexpression of an energy-dependent plasma 40$5 min, P(0.05) and volume of distribution (from membrane transport protein, known as P-glycoprotein, which acts as an efflux pump for certain endogenous Cremophor and Tween 80 caused intermediate effects compounds and xenobiotics . P-glycoprotein has on these parameters that were statistically significant been demonstrated in the cell membranes of many for total clearance, half-life, and volume of distribution.
human tumours as well as normal tissues such as the Cremophor had no adverse effect on liver function, adrenal, liver and small intestine as well as endothelial whereas Tween 80 caused haemolysis and cholestasis.
cells and haemopoietic stem cells .
The initial high-dose Cremophor perfusate concentra- Many compounds are capable of reversing the MDR phenotype in vitro by inhibiting the function of P-glycoprotein. These MDR modulators, or chemosen-sitizers, share some common structural features and Research Division, Peter MacCallum Cancer Institute, St. Andrew’s include certain calcium channel blockers, quinolines, Place, East Melbourne, Victoria 3002, Australia steroids, antioestrogens, and cyclosporins. There havebeen many clinical trials in which a chemosensitizer N.A. CrinisPathology Department, Peter MacCallum Cancer Institute, East has been combined with standard cancer chemother- apy regimens in an attempt to modulate MDR .
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