Phosphatidylcholine association increases the anti-inflammatory and analgesic activity of ibuprofen in acute and chronic rodent models of joint inflammation: relationship to alterations in bioavailability and cyclooxygenase-inhibitory potency.

We investigated whether chemical association of phosphatidylcholine (PC) to ibuprofen enhances the anti-inflammatory/analgesic activity of the nonsteroidal anti-inflammatory drug (NSAID) and whether any change in therapeutic action is due to alterations in drug bioavailability and cyclooxygenase (COX) inhibitory activity. Acute/chronic joint inflammation was induced in rats, by injection of Complete Freund's Adjuvant. In the acute study, rats were administered saline, ibuprofen, or PC-ibuprofen (at NSAID doses of 10, 25, and 50 mg/kg), and 2 h later the pain threshold of the affected joint to pressure was measured. PC-ibuprofen increased the pain threshold at all NSAID doses, whereas unmodified ibuprofen demonstrated analgesic activity at only the highest dose. In the chronic study, we investigated the effects of saline, PC-ibuprofen, and ibuprofen (administered at 15 and 25 mg/kg/day) on ankle thickness and pain threshold, and demonstrated that PC-ibuprofen had significantly greater anti-inflammatory and analgesic activity than ibuprofen, over a 30- to 60-day period. PC association resulted in reduced uptake (decreased Cmax), a modest increase in the area under the curve, and a longer t(1/2) of ibuprofen. We also demonstrated that PC-ibuprofen was a comparable or a more effective inhibitor of both 6-keto-prostaglandin F1alpha concentration of fluid collected from tissue in and around the inflamed stifle joint, and COX-2 activity in activated human umbilical vein endothelial cells. In conclusion, we have demonstrated that PC association results in increases in ibuprofen's anti-inflammatory and analgesic activity in rodent models of acute and chronic joint inflammation, and this effect may relate to alterations in drug bioavailability and COX-inhibitory potency.

Pharmacokinetic study of radioactive antineoplaston A10 following oral administration in rats.

Radiolabelled (3H-labelled) Antineoplaston A10 was administered in a single dose of 220 mg to 230 mg/kg to female Sprague Dawley rats. Blood and urine samples for determination of radioactivity were collected one hour prior to, and then at different time intervals after, the administration of the drug. Rats were sacrificed 6 h or 36 h later for the study of radioactivity in the various organs. The concentration of radioactivity in blood reached a maximum after 2 to 3 h after the administration of Antineoplaston A10, whereas the highest concentration of radioactivity in urine was observed in the 3.5-h to 4-h samples. It was observed by quantitative HPLC analysis that in rats sacrificed 6 h after Antineoplaston A10 administration, between 61% to 69% of the drug was absorbed, whereas between 37% to 28% was found in the stomach and between 2% to 3% was present in the intestinal contents and faeces. After 36 h, none could be detected in the stomach, intestinal contents or faeces. Organ distribution studies indicated greater accumulation of radioactivity in ileum, bladder, duodenum, kidneys and jejunum, and relatively low accumulation in the heart, lung, liver and brain. The concentration of radioactivity after 36 h was very low. By quantitative measurement, between 40% to 42% of the drug was excreted in the urine in 6 h and 75% of the radioactive material was in the form of Antineoplaston A10. The identification of the major radioactive material as Antineoplaston A10 was confirmed by TLC and analysis of the products of acid hydrolysis and by determination of melting range.

Preclinical studies on antineoplaston A10 injections.

Antineoplaston A10 (3-phenylacetylamino-2, 6-piperidinedione) has poor solubility in water. In order to make it more soluble for the preparation of Antineoplaston A10 injections, the compound has to be converted into its sodium salt. It was found that during neutralization A10 undergoes basic hydrolysis with formation of two components, IIa and IIb. However, A10 was found to be fairly resistant to acid hydrolysis at room temperature. At a higher temperature (110 degrees C) the reaction proceeded easily and after 60 min the compound was completely hydrolysed. The ratio of 4:1 of products of basic hydrolysis remained very constant in a number of experiments. They were subsequently identified as phenylacetylglutamine and phenylacetylisoglutamine. A similar ratio of these two compounds was found during partial hydrolysis of A10 in simulated pancreatic juice, indicating a possibility that at least some of the anticancer effects of A10 are attributable to the action of these two degradation products. A decision was therefore made to produce a formulation of Antineoplaston A10 injections, 100 mg/ml as a 4 : 1 mixture of sodium salts of phenylacetylglutamine and phenylacetylisoglutamine. This formulation did not show any significant toxic effects when tested for one year in chronic toxicity studies in a group of 160 HA/1CR Swiss white mice.