Using motivational interviewing to promote adherence to antiretroviral medications: a randomized controlled study.

The primary aim of this study was to test an intervention to support antiretroviral medication adherence among primarily low-income men and women with HIV. The study was a randomized controlled trial (Get Busy Living) with participants assigned to treatment (Motivational Interviewing [MI]) and control groups. Participants were recruited from an HIV/AIDS clinic in Atlanta, Georgia, US. Of those referred to the study, 247 completed a baseline assessment and were enrolled with 125 randomized to the intervention group and 122 to the control group. Participants were patients beginning antiretroviral therapy or changing to a new drug regimen. The intervention consisted of five MI sessions delivered by registered nurses in individual counselling sessions. Participants were paid for each session attended. The intervention sought to build confidence, reduce ambivalence and increase motivation for ART medication-taking. Medication adherence was measured by the Medication Event Monitoring System (MEMS) from the time of screening until the final follow-up conducted approximately 12 months following the baseline assessment. Participants in the intervention condition showed a trend towards having a higher mean percent of prescribed doses taken and a greater percent of doses taken on schedule when compared to the control group during the months following the intervention period. This effect was noted beginning at about the eighth month of the study period and was maintained until the final study month. Although the finding was weaker for overall percent of prescribed doses taken, the results for the percent of doses taken on schedule suggests that the MI intervention may be a useful approach for addressing specific aspects of medication adherence, such as adherrence to a specified dosing schedule.

Cellular association and cytotoxicity of doxorubicin-loaded immunoliposomes targeted via Fab' fragments of an anti-CD74 antibody.

The purpose of our research was to evaluate in vitro therapeutic efficacy of doxorubicin (DXR)-loaded immunoliposomes with Fab' fragments of the anti-CD74 antibody LL1 attached to the surface. LL1 is well suited for targeting purposes because it is internalized very fast by B-lymphoma cells. However, at in vivo application whole antibodies show fast clearance in circulation. Taking this fact into consideration, this study was initiated to elucidate the prospects of using Fab' fragments of LL1 in stead of the whole antibody for future targeting in vivo of DXR-loaded liposomes. The Fab' fragments were covalently attached to the surface of sterically stabilized liposomes by use of a PEG-based heterobifunctinal coupling agent. LL1 Fab' conjugated sterically stabilized DXR liposomes showed approximately six times faster accumulation of the drug in Raji human B-lymphoma cells than nontargeted liposomes. In vitro cytotoxicity, quantitated by a tetrazolium assay, against Raji cells gave IC(50) values of 0.13, 0.45, and 0.11 microM for DXR-loaded immunoliposomes, DXR-loaded liposomes and free drug, respectively. The results from this study suggest that DXR-loaded immunoliposomes targeted with Fab' fragments from the anti-CD74 antibody LL1 could be a useful system for future in vivo experiments.

Preparation of drug-low density lipoprotein complexes for delivery of antitumoral drugs via the low density lipoprotein pathway.

The receptor-mediated assimilation of low density lipoprotein (LDL) by many cancer cells is much higher than that of normal cells. This fact suggests that lipoproteins with incorporated cytotoxic drugs may be used as a carrier for chemotherapeutic agents to neoplastic cells. In this study a lipophilic cytotoxic compound is incorporated into reconstituted LDL by two different methods. Both the structure and cellular uptake were found to be similar to those of native LDL. Tests of the cytotoxic activity on cultured cells demonstrated that the drug delivered to the cells via the LDL pathway was able to kill 100% of the cells. Heparin and a low temperature, which are known to inhibit uptake of LDL by the receptor mechanism, abolished the cytotoxic activity of the drug-lipoprotein conjugates. The results suggest that it may be possible to use reconstituted LDL as a vehicle for lipophilic antineoplastic drugs in order to increase the drug accumulation and selectivity in tumor cell populations with high LDL receptor activity.

Incorporation of cholesterol into apolipoprotein A-I-dimyristoylphosphatidylcholine recombinants.

Apolipoprotein A-I (apoA-I) spontaneously associates with dimyristoylphosphatidylcholine (DMPC) liposomes to form discoidal high-density lipoprotein (HDL) recombinants. The uptake of cholesterol by this model HDL was studied by incubation with Celite-dispersed cholesterol. Separation of the resulting complexes by gradient centrifugation and gel filtration showed a heterogeneous distribution of particle size and composition as a consequence of the disruption and rearrangement of the recombinants. Quantitation of the amount of cholesterol taken up gave values between about 28 and 40 mol% cholesterol for the fractions within the protein peaks; the fractions with the lowest DMPC/apoA-I ratios had the lowest cholesterol contents. In another set of experiments, the association of apoA-I with DMPC-cholesterol liposomes was shown to result in complexes with characteristics similar to those obtained by the cholesterol-uptake experiments. Low concentrations of cholesterol in the liposomes enhanced the rate of lipid-protein association, but larger amounts decreased the yield of complexes by making the process thermodynamically and kinetically unfavorable. The enthalpy of recombinant formation increased with decreasing lipid/protein ratio and increasing cholesterol content, and became endothermic at about 23 mol% cholesterol. The effect of cholesterol on the thermal properties of HDL recombinants suggests that cholesterol is partially excluded from the boundary region adjacent to apoA-I. It is concluded that discoidal HDL recombinants, as a model for 'nascent' HDL, can acquire substantial amounts of cholesterol, which may be of great physiological importance for the reverse cholesterol transport and prevention of atherosclerosis.

The transfer of lipids from protein-free lipoprotein models to human fibroblasts in culture.

Lipid microemulsions were prepared by sonication of mixtures of cholesteryl ester, triacylglycerol, phosphatidylcholine and cholesterol in aqueous dispersions and were purified by gel filtration. The resulting emulsion particles were characterized by differential scanning calorimetry, electron microscopy and analytical gel filtration and were shown to have the size and general organization of low-density lipoprotein. The lipid microemulsions were used as protein-free plasma lipoprotein models for studies of the receptor-independent transfer of lipids to human fibroblasts in culture. The transfer rate of [3H]cholesterol increased with the donor concentration and with the molar ratio between cholesterol and phosphatidylcholine in the donor particles. A maximal transfer value of 1 nmol per mg protein per h was obtained for cholesterol/phosphatidylcholine 1:1 particles. There was a profound temperature effect on the cholesterol transfer. The effect of altering the core lipid of the emulsion particles on the [3H]cholesterol transfer rate was small giving a somewhat higher rate with cholesteryl oleate and cholesteryl stearate than with cholesteryl linoleate. Addition of trioleoylglycerol to the cholesteryl ester core had no effect on the transfer rate. The transfer rate of palmitoyl[14C]oleoylphosphatidylcholine was found to be about 1/5 of that obtained for [3H]cholesterol. About 50% of the cell-associated [14C]cholesteryl oleate was found in the trypsin-releasable pool, while 25% was internalized by the cells at a rate of 0.06 nmol X mg-1 X h-1. Trioleoylglycerol was internalized at the same rate as the cholesteryl ester. Our data suggest that the lipoprotein lipid composition may play a role in the receptor-independent cellular uptake of cholesterol.

Effect of substrate properties on the activity of lysosomal cholesteryl ester hydrolase.

The effects of the substrate properties on the catalytic activity of lysosomal cholesteryl ester hydrolase from rat liver have been examined with three standard substrate types: vesicle, micelle and emulsion. The pH optimum of the enzyme coincided to 4.5--5.0 with the substrate types employed. The apparent Km values were 15.3, 14.3 and 7.3 microM for vesicle, micelle and emulsion substrates, respectively. In the systems used in this study reaction products, cholesterol and oleic acid, and the nonionic surfactant Tween 80 and Triton X-100 Had an inhibitory effect. The emulsifier phosphatidylcholine and the charged phospholipid phosphatidic acid stimulated the activity. The mixed micelle of sodium taurocholate and phosphatidylcholine was the most potent substrate vehicle. With dipalmitoyl phosphatidylcholine vesicles the enzyme showed maximal activity at the gel-liquid-crystalline transition temperature of the phospholipid. The possible physiological significance of the lysosomal cholesteryl ester hydrolase is discussed with special reference to the form of the substrate.

Conjugation of apolipoprotein B with liposomes and targeting to cells in culture.

Mixed phospholipid/cholesterol (2:1 molar ratio) liposomes were conjugated with native and acetylated apolipoprotein B (apoB), the protein part of low density lipoprotein (LDL). The objective was to increase the specificity of the cellular uptake of liposomes by utilization of the LDL and scavenger receptor pathways. The method of choice for the conjugation of liposomes with apoB proved to be the detergent solubilization and removal procedure. Two detergents were tested;sodium cholate (NaC) and octyl glucoside (OG). The integrity of the resulting complexes was demonstrated by Sepharose CL-4B gel chromatography and Metrizamide gradient centrifugation. The conjugates showed a good physical stability and the leakiness was only marginally larger than for unconjugated liposomes. The interaction of apoB- and acetyl apoB-liposome conjugates with CV-1 and J774 cells, respectively, was monitored by an encapsulated pH-sensitive fluorophore, pyranine (8-hydroxy-1,3,6-pyrenetrisulfonate (HPTS)). This dye provides means of detecting binding and endocytosis of conjugates in living cells. The internalization was a fast process and about 10-times faster for the OG-conjugates than for the corresponding unconjugated liposomes. The conjugates showed a clear concentration-dependent association of dye with cells, while this was less prominent with liposomes. The uptake was nearly an order of magnitude faster with CV-1 cells than with J774 cells. Acidification of intracellular conjugates proceeded fast during the first 30 min of incubation and reached a minimum value of approx. pH 6 after 3 h. The specificity of binding of apoB-liposome conjugates to CV-1 cells was demonstrated by displacement experiments with native LDL. The results indicate that apoB-liposome conjugates may be used as a delivery vehicle for bioactive subtsances to cells.

Transfer of [3H]cholesterol between lipid vesicles and rat arterial smooth muscle cells in vitro.

Unesterified [3H]cholesterol is rapidly transferred between cholesterol-phosphatidylcholine vesicles and rat arterial smooth muscle cells in vitro. Exchange rate is influenced by the vesicle/cell ratio in a saturable way. The maximal transfer of cholesterol, which is 3.76 micrograms per mg cell protein during 4 h, is achieved with a vesicle/cell ratio of 3.4 X 10(7). Bovine serum albumin enhances the exchange by a factor of 4.5 compared to a protein-free system. The activation energy for the process is + 38.5 kJ X mol-1 with vesicles of 1:1 mole ratio of cholesterol to phosphatidylcholine (C/P). A fraction of the incorporated free [3H]cholesterol is esterified within 4 h with donor vesicles of over 1:1 C/P. When cells were incubated with vesicles of low C/P mole ratio (1:2) a fraction of the incorporated free [3H]cholesterol was esterified within 16 h. Our results are compatible with the aqueous diffusion mechanism of cholesterol exchange. Furthermore, we suggest that, in rat smooth muscle cells, the cell membrane cholesterol pool is not metabolically isolated from internal cholesterol pools, at least as judged by the ability of the cells to esterify incorporated free cholesterol.

Intracellular transport and esterification of exchangeable cholesterol in cultured human lung fibroblasts.

We have studied the intracellular fate of exchangeable cholesterol in a model system with lipid vesicles (cholesterol/phospholipid mole ratio 1:1) and cultured human lung fibroblasts. Exchangeable [3H]cholesterol in lipid vesicles was readily incorporated into cellular plasma membranes and transported to intracellular esterification sites. The formation of [3H]cholesteryl esters was not affected by cytoskeleton-disrupting drugs. A reduction of cellular pinocytosis by 75% did not reduce the formation of tracer-labelled esters, suggesting that membrane flow due to the energy-dependent pinocytosis is no major contributor to the intracellular transport of molecular cholesterol between plasma membranes and esterification sites. The formation of [3H]cholesteryl esters was not significantly affected by energy poisons (NaF and KCN) but was inhibited (to 50%) by chloroquine at 50 microM. This may indicate that membrane-derived cholesterol passes through the lysosomal compartment on its way to intracellular esterification sites.

Effect of substrate physical state on the activity of acid cholesteryl ester hydrolase.

The effects of the physicochemical properties of the substrate vehicle on the activity of acid cholesteryl ester hydrolase (ACEH; EC 3.1.1.13) isolated from rat liver lysosomes have been studied. In particular, the influence of the physical state of the neutral lipid core of substrate emulsion particles on the enzymatic activity has been probed in the light of previous studies on the clearance of cholesteryl esters (CE) from lipid-loaded cells which indicated that inclusions that are in the isotropic (liquid) state can be hydrolyzed faster than those in the anisotropic (liquid-crystalline) state. In the present study, such lipid inclusions were isolated from cultured cells and used as substrates for the hydrolase. No appreciable difference between the hydrolysis rates of isotropic and anisotropic inclusions was observed; the Vmax values were 93.0 +/- 6.7 and 84.0 +/- 3.3 nmol CE/mg.h, respectively. To elucidate the factors which affect the activity of ACEH, model inclusions were prepared by sonication and used as substrates. The physical state of these models was varied in a systematic way by changes of droplet composition and incubation temperature. The rate of hydrolysis was found to be insensitive to the physical state of the core of the model inclusions in good agreement with the results obtained with cellular inclusions. However, the activity of ACEH is sensitive to such interfacial properties of the lipid droplets as surface area available to the enzyme, net surface charge and surface solubility of the substrate CE molecules. The enzymatic activity is also sensitive to the amount of free cholesterol present in the emulsion droplets. The interfacial concentration and molecular packing of substrate CE molecules in the droplet surface significantly affect the hydrolytic activity of ACEH.

Epidemiology of Pneumocystis carinii pneumonia in an era of effective prophylaxis: the relative contribution of non-adherence and drug failure.

OBJECTIVE: To determine the relative contribution of patient non-adherence, provider failure to prescribe prophylaxis, and drug failure to the continued occurrence of Pneumocystis carinii pneumonia (PCP), and to determine correlates of non-adherence. DESIGN: Retrospective case-control study. METHODS: Patients with confirmed or presumptive PCP from May 1995 to September 1997 who had at least 6 months of prior HIV care (cases) were compared to controls matched for initial CD4 cell count and date of initial HIV care. RESULTS: The incidence of PCP declined by 85% in the 28 months of the study. Of the 118 cases of PCP identified, 59 (50%) were in HIV care for > 6 months prior to PCP diagnosis. In a multivariate logistic regression model, risk factors for PCP among patients in HIV care were patient non-adherence [odds ratio (OR), 12.4; 95% confidence interval (CI), 6.4-23.5], use of prophylaxis other than trimethoprim-sulfamethoxazole (OR, 27.0; 95% CI, 13.8-52.9), and absence of antiretroviral use (OR, 7.5; 95% CI, 4.5-12.5). Provider non-adherence occurred in one out of 59 cases (2%), and five out of 106 controls (5%). Of the patients who developed PCP on prophylaxis, 18 cases (30%) appeared due to drug failure; there were no cases of apparent drug failure among patients on trimethoprim-sulfamethoxazole. In multivariate analysis, non-adherence was more common among patients of non-white race, those with a history of injecting drug use, and those with active substance abuse or psychiatric illness. CONCLUSIONS: Patient non-adherence was the most common reason for the occurrence of PCP among patients in HIV care; provider non-adherence was uncommon. Drug failure occurred only among patients on prophylaxis other than trimethoprim-sulfamethoxazole.

Chemical composition and physical state of lipid deposits in atherosclerosis.

The composition, morphology, and physical properties of lipids in atherosclerotic lesions from human aortas were studied in order to elucidate the factors for the accumulation of cholesterol and its esters in the vessel wall. Lesions were classified histologically into 3 groups: fatty streak, fibrous plaque, and advanced plaque. The relative lipid composition of the lesions was plotted on the phase diagram of the 3 major lipids: cholesterol, cholesteryl ester, and phospholipid. Early fatty streaks had compositions within the 2-phase zone with a cholesterol-phospholipid liquid crystalline phase and a cholesteryl ester oily phase. Advanced fatty streaks and fibro-fatty plaques fell within the 3-phase zone with excess free cholesterol. Advanced plaques also had an average lipid composition within the 3-phase zone, but with a larger excess of free cholesterol. From the lipid-chemical point of view there is a continuous progression from early fatty streaks through advanced fatty streaks and fibro-fatty plaques to advanced plaques. In fatty streaks the cholesteryl esters accumulate in the form of isotropic and anisotropic droplets. The latter are in the smectic liquid crystalline state with the molecules arranged in layers and have surfaces that are spherical and smooth. Fibrous and advanced plaques showed beside droplets also amorphous lipids and cholesterol monohydrate crystals. Some of the amorphous lipids were solid up to about 45 degrees C and exhibited a smectic phase at cooling, indicating cholesteryl esters as the major component. The transition temperatures of high-melting cholesteryl esters, e.g. palmitate, are depressed by low-melting ones. Most of the triglycerides are present in the cholesteryl ester droplets and abolish the cholesteric liquid crystalline phase.

Accumulation and mobilization of cholesteryl esters in cultured human fibroblasts exposed to free cholesterol-rich phospholipid vesicles.

The uptake of free cholesterol (FC) into cells by surface transfer and its esterification to cholesteryl esters (CE) has been studied with a system of FC-egg phosphatidylcholine (EPC) vesicles and human lung fibroblasts in serum-free growth medium. The influx of FC was dependent on the molar ratio of FC to EPC in the donor vesicles. The FC incorporated by surface transfer was available for esterification in the cells. Incubations with FC/EPC vesicles with a FC/EPC molar ratio of 0.5: 1 gave a small net decrease in cellular CE, while 1:1 vesicles gave a mild increase. When the cells were incubated with 2:1 FC/EPC vesicles an extensive accumulation of CE was demonstrated, which was accentuated if albumin was present in the medium. The CE accumulated in the form of lipid droplets within the cells. The largest of these droplets exhibited positive birefringence with formée crosses, that is typical for liquid crystals of cholesteryl esters. If cells loaded with CE were incubated with vesicles with low FC/EPC ratios a net efflux of CE was noted. The present study demonstrates that the uptake of FC from lipid vesicles by surface transfer can reproduce typical features of foam cells in early atherosclerosis.

Candida epiglottitis in an adult with acute nonlymphocytic leukemia.

A 40-year-old white woman presented with fever, otalgia, and odynophagia and was found to have a peripheral white blood cell count of 90,000/mm3. A diagnosis of acute myelogenous leukemia was made. Further evaluation of symptoms and source for fever led to the diagnosis of Candida albicans epiglottitis. This is the first reported case of fungal epiglottitis in an immunocompromised adult.

Diagnostic fiberoptic bronchoscopy and protected brush culture in patients with community-acquired pneumonia.

A model for performing fiberoptic bronchoscopy as a supplement to noninvasive diagnostic methods, in patients with community-acquired pneumonia, was prospectively studied. Twenty-four patients underwent bronchoscopy, seven pilot patients and 17 of 277 (6 percent) consecutive patients with CAP. Indications for FOB were early therapy failure (less than or equal to 72h)(n = 7), late therapy failure (greater than 72h)(n = 11), or before start of antibiotic therapy in severely ill or immunocompromised patients (n = 6). Samples were obtained by aspiration of bronchial secretion and with a protected brush catheter from which quantitative cultures with a detection level of 10(4) colony forming units per ml were performed. Results concluded that FOB, with the use of quantitative PB-cultures, offered a safe and specific diagnostic tool, which on special indications, can be of great value in the management of patients with CAP.

Neonatal Proteus meningoencephalitis. Case report.

Proteus is an uncommon pathogen in neonatal meningitis and has, to our knowledge, not previously been described from Scandinavia. Our case illustrates the typical course of the disease when onset is within the first two weeks of life. The typical patient is a previously healthy, sometimes slightly preterm infant, who develops multiple brain abscesses and has a very poor prognosis. In cases with a later onset, factors predisposing for infection are common and the outcome is less severe. Our patient was a girl born at a gestational age of 36 full weeks, who was a little less alert than normal during the first three days and then became dramatically sick with convulsions and apnoeas. She died at the age of six days with severe brain damage.

Assembly of prednimustine low-density-lipoprotein complexes and their cytotoxic activity in tissue culture.

The lipophilic anticancer drug prednimustine was incorporated into model low-density-lipoprotein (m-LDL) using a novel modified method. The major steps of this procedure involve the preparation of a microemulsion containing the drug and the complexing of this emulsion with apolipoprotein B (apo B) that has been delipidated by heptane extraction. The resulting particles contained on average 338 mol prednimustine/mol apoB and exhibited a diameter that was ca. 2.5 times that of native LDL. The cellular binding, uptake, and metabolism of the complexes were found to be similar to those of native LDL. The cytotoxic activity of the complexes was monitored in vitro against T-47D breast cancer cells and normal 3T3 fibroblasts. The activity of prednimustine in m-LDL against T-47D cells after 24 h treatment was nearly 50% higher than that of the free drug, whereas in 3T3 cells the difference was relatively small. The results indicate that it is possible to target drug/m-LDL complexes to cancer cells exhibiting high LDL-receptor activity.

Pharmacokinetics of total and free valproic acid during monotherapy in infants.

The pharmacokinetics of free and total valproic acid (VPA) in plasma and whole blood after oral administration during steady state was investigated in seven infants (mean age 10.7 months) receiving monotherapy. The VPA concentrations in whole blood closely followed those in plasma but at a reduced level. A positive correlation was found between dose and mean plasma concentration (r = 0.71). Mean terminal half-lives were similar in plasma and whole blood (12.5 and 15.5 h, respectively), but were considerably longer than for free VPA (6.4 and 6.5 h, respectively; P less than 0.01). There was a significant decrease in half-lives with increasing age (P less than 0.05). Plasma and whole blood clearance for total VPA was higher than reported in older infants and adults (17.8 and 28.9 ml/kg per hour) and was considerably higher for free VPA (127.6 and 188.8 ml/kg per hour, respectively). The increase in clearance compared with that in older subjects is well in concordance with a lower protein binding of VPA (mean 85.3%). Of special importance is that the percentage of unbound VPA increased with increasing concentrations of total VPA. The fraction of unbound VPA in plasma increased even more in subjects with low albumin concentrations (P less than 0.01).

Plasma concentrations of valproate during maintenance therapy in epileptic children.

A total of 20 children with various types of epilepsy were treated with valproate, 11 with monotherapy and 9 with valproate in combination with phenobarbitone, phenytoin, or carbamazepine. Valproate was given either every 8 or 12 h. At least two different dose levels were tried in each patient. The pharmacokinetics of valproate during the interval between doses was determined using a gas chromatographic technique. The clinical effect of the treatment was assessed by interviewing the parents. The plasma concentrations showed considerable fluctuation during the intervals between doses. The mean increase from pre-administration to peak level was 82% when the dose interval was 12 h, and 62% when it was 8 h. The mean plasma half-life of valproate, using a one-compartment model, was 10.9 +/- 1.3 h (mean +/- SD). The plasma half-life of valproate was decreased when the drug was combined with the other anti-epileptics. The calculated area under the concentration versus time curve was linearly related to dose, both in a single patient on four dose levels and when different patients were compared. The clinical effect of valproate monotherapy was best in patients with absences, usually good in myoclonus and less favourable in other types of epilepsy. For children with absences, the optimal dose range of valproate was between 20 and 40 mg/kg/24 h. In comparison, the myoclonic types of epilepsy needed a slightly higher dose level, between 30 and 60 mg/kg/24 h. In the latter group a "therapeutic window" seems to exist, since patients below and above the suggested dose levels were not well-controlled. Therapeutic monitoring of valproate does not appear meaningful when the drug is used as monotherapy. However, in combination therapy, determination of the plasma levels of all anti-convulsants used may be helpful. The large fluctuations of valproate during a dose interval must be taken into consideration when the clinical effects are analysed.

A lipophilic paclitaxel derivative incorporated in a lipid emulsion for parenteral administration.

Paclitaxel is one of the most effective and most widely-used anti-cancer agents. However, paclitaxel is difficult to formulate for parenteral administration because of its low aqueous solubility and Cremophor EL, the excipient used for its formulation, has been shown to cause serious side effects. This study reports an alternative administration vehicle involving a lipophilic paclitaxel derivative, paclitaxel oleate, incorporated in the core of a nano-size sterically stabilized oil-in-water (o/w) lipid emulsion. This lipid emulsion, with a particle size of 50 nm, has many favourable properties such as drug-carrier like biocompatibility, physical stability and ease of preparation. When paclitaxel in Cremophor EL/ethanol and paclitaxel oleate in emulsion were incubated with plasma a greater proportion of paclitaxel was found in the lipoprotein pool when formulated as paclitaxel oleate in a lipid emulsion compared to unesterified paclitaxel. The paclitaxel prodrug, paclitaxel oleate, demonstrated cytotoxic activity against cultured HeLa cells and with a marked increase in activity with incubation time. The 50% inhibition (IC(50)) was calculated to be 5500, 500, 150, and 100 nM for 24, 48, 72, and 96 h, respectively. Pharmacokinetic data, obtained with rabbits, showed significantly greater AUC, higher C(max), lower systemic clearance and lower V(ss) when paclitaxel was formulated as an oleate prodrug in a lipid emulsion than when formulated in Cremophor EL/ethanol. The formulated emulsion may be clinically useful not only for eliminating toxic effects of Cremophor EL but also for improvement of the pharmacokinetic parameters of paclitaxel.