Disease relevance of Avlinox

• Complement activation by Cremophor EL as a possible contributor to hypersensitivity to paclitaxel: an in vitro study [1].
• Cremophor EL, solvent for paclitaxel, and toxicity [2].
• Human breast cancer MCF-7 wild-type (WT) and resistant (TH) cell lines were cultured in whole human plasma to study anthracycline retention after treatment with different combinations of PTX, Cremophor EL (CEL) (PEG35 castor oil; BASF, Parsippany, NJ), and DOX [3].
• CONCLUSIONS: From the results obtained in this study, it is concluded that exposure to paclitaxel but not Cremophor EL is associated with peripheral neuropathy development [4].
• The Cremophor EL-induced cholestasis was an immediate and reversible phenomenon, since at 30-35 min after drug injection all parameters evaluated had returned to control values [5].

High impact information on Avlinox

• Experiments with one or more individual sera indicated the above effect was due to Cremophor EL plus ethanol, that increased formation of Bb also occurred, that the drug-induced rise in SC5b-9 was inhibited by sCR1, and that EGTA/Mg2+ partially inhibited SC5b-9 formation and stimulated Bb formation [1].
• The clinical formulation of paclitaxel contains 50% Cremophor EL, a polyethoxylated castor oil vehicle (carrier) that can reverse multidrug resistance (MDR) mediated by P-glycoprotein [6].
• Measurement of cremophor EL following taxol: plasma levels sufficient to reverse drug exclusion mediated by the multidrug-resistant phenotype [7].
• We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA [8].
• These data demonstrate that Cremophor EL has a profound effect on the pharmacokinetics of paclitaxel im mice [9].

Chemical compound and disease context of Avlinox

• To explore the role of complement in the observed hypersensitivity reactions, we studied the effects of paclitaxel and Cremophor EL plus ethanol on human complement in vitro [1].
• All patients received prophylaxis for hypersensitivity reactions, related to Cremophor-EL, with steroids and histamine antagonists [10].
• As both Cremophor EL and paclitaxel are neurotoxic, we evaluated their pharmacodynamic effects on the development of peripheral neuropathy as the most important nonhematologic toxicity [4].
• Pharmacologically active in vivo doses of P-glycoprotein (Pgp) blockers, specifically verapamil, Cremophor EL and PSC833 cause toxicity in addition to that from the concomitantly used cancer chemotherapeutic drugs [11].
• Nude mice bearing s.c. D456 MG glioblastoma xenografts were injected i.p. with 10-30 mg/kg O6-benzylguanine dissolved in either 40% PEG 400/saline or 10% cremophor-EL/saline [12].

Biological context of Avlinox

• The purpose of the present study was to characterize the distribution and elimination kinetics of the paclitaxel vehicle Cremophor EL (CrEL), a polyoxyethylated castor oil that can modulate P-glycoprotein-mediated multidrug resistance in vitro [13].
• Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel [14].
• PURPOSE: The shortening of infusion time from 3 to 1 hour decreases the systemic exposure (area under the curve, AUC) of total and unbound paclitaxel but increases the AUC of its vehicle Cremophor EL, whereas the time above total paclitaxel concentrations of 0.05 micromol/L (T >0.05) remains almost constant [4].
• We mixed PCT with either a biodegradable polymeric solubilizer, HySolv, or Cremophor EL for bimonthly systemic treatments and injected water-soluble lipopolymer (WSLP)/p2CMVmIL-12 (plasmid encoding IL12 gene) complexes locally every week [15].
• We investigated the effects of Cremophor-EL on the cardiac output (CO); mean arterial pressure (MAP); and hepatic, renal and pancreatic blood flow in the anesthesized canine model [16].

Anatomical context of Avlinox

• A similar Cremophor EL-induced increase in DNR uptake was also observed in an unrelated MDR cell line derived from K562 cells [17].
• Also Cremophor EL did not increase the sensitivity of normal bone marrow progenitor cells cultured in vitro to high concentrations of vinblastine [17].
• Vascular endothelium was gently removed from the common carotid artery of 10 New Zealand White rabbits that then were treated with therapeutic doses of cyclosporine A (15 mg/kg/day), or its vehicle (Cremophor-EL) [18].
• This hypothesis was tested by studying vWF release from human umbilical vein endothelial cells primed with either CsA or cremophor EL [19].
• At a concentration of 0.005% (v/v), Cremophor EL halved the number of cells that extended neurites after 48 hr in serum-free medium [20].

Associations of Avlinox with other chemical compounds

• Verapamil and Cremophor EL block P-glycoprotein-mediated efflux of "natural product" drugs and increase their accumulation in resistant cells [21].
• The cause (taxol itself or its excipient Cremophor EL; Badische Anilin und Soda-Fabrik AG [BASF], Ludwigshafen, Federal Republic of Germany) and the mechanism of these reactions to taxol are unknown [22].
• Using flow cytofluorometric analysis of daunorubicin (DNR) uptake as a measure of the expression of the MDR phenotype, Cremophor EL (1:10(3] in the growth medium increased intracellular DNR in an MDR cell line, R100 cells, to levels similar to that observed in the drug-sensitive parental cells, CCRF-CEM [17].
• These in vitro cytotoxicity results were independent of the paclitaxel diluent, a 1:1 solution of ethanol and Cremophor EL [23].
• Gradient elution was applied and provided increased robustness to ion suppression by the drug formulation vehicle (polysorbate 80 and Cremophor EL) [24].

Gene context of Avlinox

• Neither CYP3A nor PGP levels in liver were altered by paclitaxel or Cremophor EL treatment at the 24-h and 96-h time points [25].
• Cremophor EL, a carrier solvent for paclitaxel, also caused elevated CYP2C activity [25].
• Modulation of P-glycoprotein function was performed by verapamil or Cremophor EL [26].
• We used verapamil, PSC833 and Cremophor EL as Pgp modulators, which affect the function of Pgp by different mechanisms [27].
• Cremophor EL reversed multidrug resistance in vitro but not in tumor-bearing mouse models [28].

Analytical, diagnostic and therapeutic context of Avlinox

• Cremophor EL levels were determined by a novel high-performance liquid chromatography procedure [9].
• PATIENTS AND METHODS: Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions [29].
• Cremophor EL may prove to be a relatively pharmacologically inactive addition to chemotherapeutic protocols which may be able to reverse the MDR phenotype in tumors and also help to prevent the selection of MDR cell variants from within a tumor cell population during chemotherapy [17].
• Undetectable Cremophor EL levels after oral administration may have a very beneficial influence on the safety of the treatment with oral paclitaxel [30].
• The absence of Cremophor EL may permit ABI-007 to be administered without the premedications used routinely for the prevention of hypersensitivity reactions [31].

References