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Biomedical subjects

David Needham

Publications and source records attributed to David Needham.

9 recordsLinked to original sources
PubMed2006

Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.

Animals↗
PubMed2006

Microdroplet dissolution into a second-phase solvent using a micropipet technique: test of the Epstein-Plesset model for an aniline-water system.

The Epstein-Plesset model was originally derived for the dissolution of a single gas bubble in an infinite aqueous solution (Epstein, P. S.; Plesset, M. S. J. Chem. Phys. 1950, 18, 1505-1509). The micropipet manipulation technique was previously shown to test this theory on air microbubbles and air-filled lipid-coated microparticles accurately and appropriately (Duncan, P. B.; Needham, D. Langmuir 2004, 20, 2567-2578). This same theory is now tested to model liquid microdroplet dissolution in a well-defined solution environment. As presented previously for the gas-bubble system, holding a single microparticle at the end of a micropipet was not shown to affect the dissolution profile and allowed isotropic diffusion significantly, a necessary condition for the validation of the theory. Here, an aniline-water system with an initial droplet diameter of 50 microm was used as a model liquid-liquid system. A microdroplet of aniline in an aqueous solution presatureated with aniline at distinct levels was tested, as was the reverse system of a water droplet in an aniline solution. The dissolution lifetime was shown to increase with increasing medium saturation fraction according to the Epstein-Plesset time-dependent theory (including the time required to establish the stationary layer) neglecting interfacial tension. The droplet lifetime can be increased by an order of magnitude (from about 10 to 100 s) by increasing the saturation fraction from 0 to 0.9 and by another order of magnitude by increasing from 0.9 to 0.99. The technique proved to be an accurate and appropriate method to test the dissolution of single liquid microdroplets in a second liquid solution and establishes a systematic experimental and theoretical approach to the investigation of the formation of polymer and other microparticles.

Aniline Compounds↗
PubMed2006

Hyperthermia mediated liposomal drug delivery.

Drug delivery systems have been developed for cancer therapy in an attempt to increase the tumour drug concentration while limiting systemic exposure. Liposomes have achieved passive targeting of solid tumours through enhanced vascular permeability, which is greatly augmented by hyperthermia. However, anti-tumour efficacy has often been limited by slow release of bioavailable drug within the tumour. Local hyperthermia has become the most widely used stimulus for triggered release of liposomal drugs, through the use of specific lipids, polymers or other modifiers. A temperature-sensitive liposome containing doxorubicin has been shown to release 100% of contents through stabilized membrane pores within 10-20 s at 41 degrees C. This formulation has exhibited dramatic improvements in pre-clinical drug delivery and tumour regression and is now in clinical trials. Significantly, recent studies show that this liposome, in combination with local hyperthermia, exhibits vascular shutdown as a mechanism of anti-tumour effect that is not observed with free doxorubicin.

Animals↗
PubMed2005

Lysolipid incorporation in dipalmitoylphosphatidylcholine bilayer membranes enhances the ion permeability and drug release rates at the membrane phase transition.

The enhanced permeability of lipid bilayer membranes at their gel-to-liquid phase transition has been explained using a "bilayer lipid heterogeneity" model, postulating leaky interfacial regions between still solid and melting liquid phases. The addition of lysolipid to dipalmitoylphosphatidylcholine bilayers dramatically enhances the amount of, and speed at which, encapsulated markers or drugs are released at this, already leaky, phase transition through these interfacial regions. To characterize and attempt to determine the mechanism behind lysolipid-generated permeability enhancement, dithionite permeability and doxorubicin release were measured for lysolipid and non-lysolipid, containing membranes. Rapid release of contents from lysolipid-containing membranes appears to occur through lysolipid-stabilized pores rather than a simple enhancement due to increased drug solubility in the bilayer. A dramatic enhancement in the permeability rate constant begins about two degrees below the calorimetric peak of the thermal transition, and extends several degrees past it. The maximum permeability rate constant coincides exactly with this calorimetric peak. Although some lysolipid desorption from liquid state membranes cannot be dismissed, dialyzation above T(m) and mass spectrometry analysis indicate lysolipid must, and can, remain in the membrane for the permeability enhancement, presumably as lysolipid stabilized pores in the grain boundary regions of the partially melted solid phase.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2004

Test of the Epstein-Plesset model for gas microparticle dissolution in aqueous media: effect of surface tension and gas undersaturation in solution.

The gas from a free air bubble will readily dissolve in water, driven by two main factors: the concentration (undersaturation) of dissolved gas in the aqueous solution and the surface tension of the gas bubble-water interface via a Laplace overpressure in the bubble that this creates. This paper experimentally and theoretically investigates each of these effects individually. To study the effects of surface tension, single- and double-chain surfactants were utilized to control and define interfacial conditions of the microbubble in saturated solution. To study the effect of undersaturation, solid distearoylphosphocholine lipid was utilized to coat the gas microparticle with, essentially, a wax monolayer and to achieve zero tension in the surface. The experimental work was performed using a micromanipulation technique that allows one to create and micromanipulate single air microparticles (5-50 microm radius range) in infinite dilution and to accurately record the size of the particle as it loses volume due to the dissolution process. The micropipet technique has shown to be an improvement over other previous attempts to measure dissolution time with a 3.2% average experimental error in gas microparticle dissolution time. An ability to study a gas microparticle in infinite dilution in an isotropic diffusion field is in line with the theoretical assumptions and conditions of the Epstein-Plesset model. The Epstein-Plesset model on average underpredicted the experimentally determined dissolution time by 8.6%, where the effect of surface tension was considered with a range of surface tensions from 72 down to 25 mN/m. The Epstein-Plesset model on average overpredicted the dissolution time by 8.2%, where the effect of undersaturation was considered for a microparticle with zero tension in the surface (zero Laplace pressure) and a range of gas saturations from 70% to 100%. Compared to previous attempts in the literature, this paper more appropriately and accurately tests the Epstein-Plesset model for the dissolution of a single microbubble and an air-filled microparticle in aqueous solution.

Gases↗
PubMed2003

Disc formation in cholesterol-free liposomes during phase transition.

Cryogenic transmission electron microscopy (cryo-TEM) images of lysolipid-containing thermosensitive liposomes (LTSL) revealed that open liposomes and bilayer discs appeared when liposomes were cycled through the gel (Lbeta') to liquid-crystalline (Lalpha) phase transition. The amount of bilayer discs generated was dependent on the combined presence of PEG-lipid and lysolipid in the membrane. We hypothesize that micelle-forming membrane components stabilize the rim of bilayer openings and membrane discs that form when liposomes are cycled through TC.

Cryoelectron Microscopy↗
PubMed2002

Evaluation of synthetic phospholipid ultrasound contrast agents.

The echogenic properties of synthetic, phospholipid encapsulated, air-filled microbubbles with various carbon-chain length as ultrasound contrast agents are investigated through the use of a flow-through laboratory ultrasound system. Specifically, we investigate the effect of shell carbon-chain length on the ultrasonic signal for a variety of flow rates. Averaged, integrated backscatter power measurements from the lipid encapsulated agents are benchmarked against those of Albunex (Albunex is a registered trademark of Molecular Biosystems, Inc., San Diego, CA), a commercially available, air-filled protein microbubbles contrast agent, approved for clinical use in echocardiography in the United States by the Food and Drug Administration. We find that the lipid encapsulated agents sustain less damage leading to gas dissolution or particle destruction as compared to Albunex in the slow-flow studies performed. The carbon-chain length of the encapsulating lipid molecule is shown not to observably affect the backscattered amplitude of ultrasound at flow velocities exceeding 7 mm/s.

Contrast Media↗