Doxorubicin Volume

If extravasation occurs, the infusion should be stopped immediately, with aspiration of fluid from the site, needle, and tubing as much as possible. The affected limb or area should be elevated (if possible). The site should be documented photographically as well as the time, date, site, patient complaints, and estimated volume of extravasated drug.36 Both hot and cold packs have been used to manage extravasations, but use of the proper therapy for certain agents is critical. For example, warm compresses have been shown to worsen doxorubicin extravasations, whereas cold packs may exacerbate vinca alkaloid... 

Stock solutions of anthracyclines (1 mg/mL) were prepared in double distilled water and stored at 4°C in the dark. Standard working solutions were prepared by diluting stock solutions with double distilled water or 0.1 M phosphoric acid. Aliquots of blank human plasma (0.5 mL) were spiked with working solutions of anthracyclines, mixed with 0.5 mL of 0.2M dibasic sodium phosphate buffer (pH 8.4), extracted with 4 mL of chloroform 1-heptane (9 1 v/v) by shaking for 15 min and centrifuged at 4000 rpm for 10 min. The lower organic layer was re-extracted with 0.25 mL of 0.1M phosphoric acid. The upper aqueous layer was collected and assayed. The injection volume was 50 fiL. Retention times for daunorubicinol, daunorubicin, idarubicinol, idarubicin, doxorubicinol, doxorubicin, epirubicinol, and epirubicin were 6,7, 9.1, 8.0, 11.3, 5.1,6.4, 5.5, and 7.0 min, respectively. 

The initial mixture and each time point are then assayed for doxorubicin and lipid. Lipid concentrations can be quantified by the phosphate assay (see above) or by liquid scintillation counting of an appropriate radiolabel. Doxorubicin is quantified by an absorbance assay (see below). The percent uptake at any time point (e.g., t = 30 minutes) is determined by %-uptake = [(D/L), =30minutes] x 100/[(D/L) inuiai]. Doxorubicin can be assayed by both a fluorescence assay and an absorbance assay, but we find the latter to be more accurate. The standard curve consists of four to five cuvettes containing 0 to 150 nmol doxorubicin in a volume of 0.1 mL samples to be assayed are of the same volume. To each tube is added 0.9 mL of 1% (v/v) Triton X-100 (in water) solution. For saturated lipid systems such as DSPC/Chol, the tubes should be heated in a boiling water bath for 10 to 15 seconds, until the detergent turns cloudy. Samples are allowed to cool, and absorbance is read at 480 nm on a UV/Visible spectrophotometer. 

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

Fig. 6. The combined effects doxorubicin and chitosan on tumor volume in sarcoma )80-bearmg mice.

For insertion into premade doxorubicin-loaded liposomes (Doxil), mix equal volumes of liposomes and lipidation reaction mixture and incubate at 37°C for 12-16 h (see Note 7). Purification of unreacted lipid and protein is not necessary at this step, because they do not interfere with insertion process and will be removed eventually by gel-filtration of decorated liposomes on Sepharose CL-4B. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

Fig. 5 Effect of treatment type on the increase in tumor volume in mice inoculated with BLSC-KU cells. The animals in treatment groups received i.v. doses of doxorubicin via tumor-specific or non-specific liposomes on day 0, 3, and 7 after the initiation of treatment. The tumor-specific and non-specific liposomes were conjugated with MoAbs against leukemia cells and normal mouse IgG, respectively. (Adapted in part from Ref. l)...

There was severe phlebitis in cancer patients receiving deferoxamine (50 mg/kg/day by intravenous infusion over 72 hours) and iron sorbitol citrate in an attempt to enhance doxorubicin activity (18). Dilution of the drug in large volumes of saline did not prevent this adverse effect. 

Plain fibers also have been used to perform in vivo measurements of drugs in minute volumes of body fluid by using conventional methods of absorptiometry [48] and fluorimetry [49], but also more sophisticated methods such as two-photon-excited fluorimetry and sequentially excited fluorimetry [49]. Detection limits of ca O.S pmol/L were determined for the drug adriamcin (doxorubicin) in interstitial fluid and whole blood and are comparable for the three... 

The consequences of liposome incorporation must be balanced. For example, loading of daunorubicin into conventional liposomes decreases the volume of distribution, increases peak concentration, and prolongs the initial rate of elimination from the plasma (Figure 8.14). The conventional liposomes are cleared from the circulation, however, producing a substantial drop in the plasma concentration of daunorubicin during the first 24 h after injection. In contrast, incorporation of doxorubicin into Stealth liposomes provides the... 

The process of drug deposition depends on the distribution volume. When a drug is associated with a carrier, the rate of drug clearance is decreased (the half-life increases), and the volume of distribution is decreased. Consequently, it promotes tumor uptake [85]. The size of the carrier (normally 5 200 mn) minimizes penetration of the drugs into the organs and renal clearance. The volume distribution of the carrier is similar to the plasma volume when the blood circulation of the drug carrier is increased and the drug release rate from the carriers is slow [2]. Therefore, this limited distribution volume increases the maximum tolerated dose (MTD), as in the case of HPMA copolymer-linked doxorubicin [86]. 

The self-assembly behavior of amphiphilic PEO(PLLA)2 mik-toarm star copolymers was examined in aqueous solutions. " Using a variety of LS and miaoscopy techniques, it was shown that vesicular stmctures were formed in a much broader range of PEO volume fractions (0.2-0.7) compared to the corresponding linear block copolymers (Figure 12). Taking advantage of this behavior, the efBdent encapsulation of the anticancer dmg doxorubicin hydrochloride was achieved. 

Polymer Preprints. Volume 41, Number 1. Proceedings of a conference held San Fracisco, Ca., March 2000. Washington D.C., ACS, Div.of Polymer Chemistry, 2000, p.992-3, 28cm, 012 IN VITRO AND IN VIVO ANTI-TUMOUR ACTIVITIES OF NANOPARTICLES BASED ON DOXORUBICIN-PLGA CONJUGATES Yoo H S Park T G... 

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