Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some well-known fatty acid ester surfactants, e.g., Cremophor EL and Solutol HS 15, are modulators of multidrug resistance in vitro and in vivo. Because they are polydisperse, and their active component(s) have not been identified, the therapeutic potential of such surfactants is unclear. To better define the active components of Solutol HS 15 and to make more potent surfactant multidrug resistance modulators, highly purified C-18 fatty acids were esterified with ethylene oxide at 5-200 molar ratios. Unexpectedly, ethylene oxide esters of pure 12-hydroxy stearic acid, the major components of Solutol HS 15, displayed negligible resistance modification activity compared with Solutol HS 15 itself or to stearic and oleic acid esters synthesized under identical conditions. Since oleic acid esters appeared to have good activity, a series of these compounds was prepared to determine the optimal ethylene oxide/fatty acid ratio. The optimal ratio was found to be 20 mole ethylene oxide: I mole fatty acid, with a steep decline in activity for products made with ratios above and below the optimum. The most active oleic acid ester, designated CRL 1337, was 8.4-fold as potent as Solutol HS 15 and over 19-fold as potent as Cremophor EL in promoting rhodamine 123 accumulation in multidrug-resistant KB 8-5-11 cells in vitro. Our results show that the structure of the hydrophobic domain (fatty acid) of surfactants as well as its hydrophile-lipophile balance are critical in determining the potency of surfactants as reversing agents.
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PMID:Comparison of solutol HS 15, Cremophor EL and novel ethoxylated fatty acid surfactants as multidrug resistance modification agents. 763 69

Taxol is a promising agent for use in ovarian cancer and other malignancies. One problem associated with taxol is its low aqueous solubility, requiring Cremophor EL (polyethoxylated castor oil) and ethanol as excipients (Diluent 12); these agents cause serious adverse effects. Liposomes containing taxol and phospholipid (in a 1:33 mole ratio, respectively) were prepared from phosphatidylglycerol and phosphatidylcholine in a 1:9 mole ratio. Antitumor effect was evaluated against Colon-26, a taxol-resistant murine tumor. Given as 1, 4, or 9 injections, free taxol given i.v. in Diluent 12 was ineffective at delaying tumor growth at doses < or = 30 mg/kg per injection (the maximum tolerated dose). In contrast, taxol-liposomes were well tolerated at doses greater than or equal to the maximum tolerated dose of free taxol and showed significant tumor growth inhibition at 10-45 mg/kg per injection.
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PMID:Antitumor effect of taxol-containing liposomes in a taxol-resistant murine tumor model. 790 97

Paclitaxel (as Taxol) is under clinical investigation for treatment of a variety of cancers. Because of its low aqueous solubility, paclitaxel is administered in polyethoxylated castor oil (Cremophor EL) and ethanol, a vehicle associated with severe hypersensitivity reactions. Cyclodextrins (CyDs) are molecular complexing agents that can increase the solubility and stability of some poorly soluble drugs and were investigated here as a means to obviate the requirement for Cremophor. A variety of beta- and gamma-cyclodextrins were tested; (hydroxypropyl)-(HP beta CyD), (hydroxyethyl)-(HE beta CyD), and dimethyl-(DM beta CyD) beta CyD increased paclitaxel solubility 2 x 10(3)-fold or more and did not alter the cytostatic properties of paclitaxel in vitro. The quantity of drug solubilized increased with the CyD concentration, but precipitation upon dilution occurred with some CyDs or stoichiometries. Thermal and spectroscopic (fluorescence, IR, NMR, and circular dichroism) analyses provided evidence of complex formation that was stable in the solid state but weak in solution, suggesting an explanation for the observed precipitation upon dilution. DM beta CyD solutions of < or = 3.7 mol % (mole of drug:mole of CyD) showed no precipitation upon dilution, nor did HP beta CyD solutions of < or = 0.14 mol %. Maximum tolerated dose (MTD) experiments showed uncomplexed DM beta CyD to be toxic in mice at doses of 2 g CyD/kg body weight, the quantity required to administer paclitaxel at 10 mg/kg. HP beta CyD allowed paclitaxel administration at higher doses and had an MTD of 25 mg drug/kg. The CyDs tested are marginal in feasibility for paclitaxel administration, and their use in taxane formulation will require a reduction of the dose-limiting toxicity of the CyD itself.
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PMID:Pharmaceutical and physical properties of paclitaxel (Taxol) complexes with cyclodextrins. 880 38