Charles Winternitz

Development of a Polymeric Surgical Paste Formulation for Taxol

AbstractPurpose. To develop and characterize a biodegradable polymeric sustained release surgical paste formulation for taxol. Methods. Taxol was incorporated into poly(ε-caprolactone) (PCL) or blends of PCL with methoxypolyethylene glycol, MW 350 (MePEG). The surgical pastes were characterized using gel permeation chromatography, thermal analysis, scanning electron microscopy, and a tensile strength tester. In vitro release data for taxol from the surgical paste formulations was carried out at 37°C in phosphate buffered saline, pH 7.4, using an HPLC assay for taxol. Antiangiogenic activity of the formulations were assessed using a chick chorioallantoic membrane assay (CAM). Results. The addition of up to 30% MePEG in PCL decreased the melting point of PCL by 5°C and the tensile strength by 152.7 N/cm2 to 26.7 N/cm2 but increased the degree of PCL crystallinity from 42% to 51%. Taxol showed a biphasic in vitro release profile composed of a burst phase lasting 1 or 2 days followed by a period of slow sustained drug release. There was no significant difference in the release profiles of taxol from two different sources of PCL. The addition of MePEG increased the amount of water taken up by the polymer blends but decreased the rate of taxol release. The formulations were shown to have antiangiogenic activity by the CAM assay at levels as low as 0.1% taxol using 3 mg surgical paste pellets. Conclusions. Our surgical paste formulations for taxol give sustained release while having physical properties which can be adjusted using additives.

Fucoidan film safely inhibits surgical adhesions in a rat model.

BACKGROUND The purpose of this study was to evaluate the in vivo efficacy of 13 compounds and to further characterize the load limiting and potential toxicity of the most efficacious compound. The cascade of biochemical and molecular events that results in the formation of postsurgical adhesions provides numerous theoretical opportunities for prophylactic intervention. METHODS Candidate agents were loaded into sodium hyaluronate (HA) films and administered to male Sprague-Dawley rats using a cecal-sidewall model of surgical adhesions. An adhesion score was obtained for each rat based on the strength and extent of the adhesions. The most efficacious agent, fucoidan, was further evaluated in a load-limiting study with a concentration range of 0.0033 to 33% w/w per film. The potential toxicity of fucoidan was evaluated in a separate study by comparison of hematology findings, blood chemistry, urinalysis, and incision thickness from rats administered control films or 33% w/w fucoidan films 1 to 4 d prior to sacrifice. RESULTS Fucoidan loaded films reduced adhesion scores by approximately 90% compared with control films (P<0.05). A total of 50% to 100% of animals were adhesion free at fucoidan film loadings of 0.33% to 33% w/w compared with all control film animals having adhesions. No adverse effects were observed from 33% w/w fucoidan films equivalent to approximately 30 mg fucoidan/kg body weight. CONCLUSIONS Local administration of fucoidan film during rat cecal-sidewall surgery safely reduced adhesion scores by approximately 90% and resulted in 50% to 100% of animals being adhesion free.

Mechanism of hemolysis of human erythrocytes exposed to monosodium urate monohydrate crystals. Preliminary characterization of membrane pores

Microcrystals of monosodium urate monohydrate (MSUM) have the ability to cause rapid hemolysis of erythrocytes. The nature of the initial MSUM crystal-erythrocyte membrane binding interaction was investigated over a range of different ionic strength media. There was negligible binding of MSUM to erythrocyte ghost membranes in low ionic strength media such as isotonic mannitol but binding was dramatically increased in isotonic NaCl/mannitol solutions or isotonic mannitol containing 1 mM Ca2+. Hemolysis induced by MSUM crystals was preceded by the leakage of K+ from the cells suggesting a colloid-osmotic mechanism of hemolysis. The inclusion of large (oligosaccharide) molecules in the extracellular media or the modulation of the extracellular solution tonicity inhibited both the rate and extent of hemolysis supporting the concept of MSUM-induced pores followed by colloid osmotic hemolysis.

The interaction of monoclinic calcium pyrophosphate dihydrate crystals with neutrophils

Monoclinic calcium pyrophosphate dihydrate (m-CPPD) crystals were synthesized and characterized using physical methods, IgG binding to m-CPPD crystals was quantitated, and the effect of IgG or plasma opsonization on m-CPPD-induced neutrophil activation was determined. Adsorption of IgG to crystals was measured using fluorescent-labelled FITC-IgG. Neutrophil activation by uncoated m-CPPD and crystals precoated with IgG or plasma was measured using luminol-enhanced chemiluminescence, superoxide anion generation, and myeloperoxidase release. m-CPPD bound small (compared to triclinic CPPD) but significant amounts of IgG and induced a strong activation of neutrophils at low concentrations of crystals. The rate and extent of chemiluminescence, superoxide anion production, and degranulation was not affected by precoating m-CPPD crystals with IgG during the early phase of neutrophil responses, but was inhibited by the precoating of crystals with plasma.