Effect of an imidazolineoxyl nitric oxide on prostaglandin synthesis in experimental shock: possible role of nitrogen dioxide in prostacyclin synthase inactivation.

The effect of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), a nitric oxide (NO) scavenger that yields nitrogen dioxide (NO(2)) in a rat endotoxemia model was investigated. Endotoxin (lipopolysaccharide [LPS]) increased NO synthase (NOS) activity and inducible NOS expression measured in lung and plasma levels of nitrite/nitrate, 6-oxo-prostaglandin (PG) F(1alpha), thromboxane B(2), and PGF(2alpha). Infusion of cPTIO significantly reduced LPS-induced mean arterial blood pressure decline and mortality and selectively reduced LPS-induced 6-oxo-PGF(1alpha) plasma levels and prostacyclin synthase (PGIS) activity measured in the lung and aorta. In vitro, PGIS activity in aorta rings was not modified by SNAP (NO donor), cPTIO slightly inhibited the enzyme but not in the presence of L-N(G)-monomethyl arginine, and SNAP in combination with cPTIO significantly inhibited PGIS. Thus, cPTIO may be beneficial in endotoxic shock because of NO scavenging and PGIS inactivation, which could be mediated by NO(2).

High-performance liquid chromatography analysis of Bobel-24 in biological samples for pharmacokinetic, metabolic and tissue distribution studies.

A rapid and simple HPLC method is described for the determination of Bobel-24 (2,4,6-triiodophenol) and other iodinated derivatives in biological samples. The sample preparation was liquid-liquid extraction before injection onto the HPLC system. 2,6-Diiodo-4-methylphenol was used as internal standard. Separation was obtained using a reversed-phase column under isocratic conditions. The mobile phase consisted of water-acetonitrile (62:38). 2,4,6-Triiodophenol was detected at 277 nm. This method was used for Bobel-24 determination in plasma, urine, synovial liquid and different tissues. The assay was applied to pharmacokinetic studies in dog and horse plasma and different dog tissues for tissue distribution profiles toxicological and metabolic studies. In addition, this method for biological samples can be applied to non-biological samples such as pharmaceutical formulations in stability studies and quality control assays.

Liposomes as carriers of different new lipophilic antitumour drugs: a preliminary report.

We studied the liposome formulation characteristics of eight new lipophilic antitumour agents that have demonstrated a broad spectrum of antitumour activity in preclinical in vitro and in vivo screening models. Multilamellar vesicles were prepared by using standard evaporation/hydration methods. The drug to lipid weight ratio was 1:15 in all cases. Different combinations of DMPC, DMPG and cholesterol were used. The quality of the liposomal formulations was evaluated by calculating the percentage drug bound to the liposome phase and assessing the morphology of the liposome phase by optic microscopy, to rule out the presence of drug crystals or drug/lipid microaggregates. Good liposomal preparations were obtained with hexamethylmelamine, penclomedine, mitindomide, and fazarabine. However, with taxol, batracylin, trimelamol, and diaziquone, the presence of crystals of free drug or microaggregates of lipid/drug complex was observed in all preparations, independently of lipid composition. In general, mixtures of DMPC:DMPG at a molar ratio between 7:3 and 9:1, and the addition of 5 per cent cholesterol (w/w) gave the optimal results. In vitro cytotoxicity studies of free and liposomal drugs against L1210 cells showed changes in both directions after liposome entrapment, thus suggesting that liposome entrapment may alter drug cellular uptake or may result in chemical modifications of the entrapped drug. Because of the limited number of compounds studied we were unable to identify general chemical characteristics required for an enhanced liposome formation and drug entrapment.