General anesthesia significantly changed whole body and regional pharmacokinetics of each local anesthetic as well as the systemic effects. General anesthesia is thus an important but frequently overlooked factor in studies of local anesthetic toxicity.

General anesthesia produced physiological perturbations, exacerbated local anesthetic-induced cardiovascular depression, and changed the pharmacokinetics of toxic doses of local anesthetics. However, cardiovascular fatalities from local anesthetics occurred only in conscious animals.

With the aim of improving the treatment of glioblastoma multiforme, we investigated the potential of thalidomide to enhance the effectiveness of cisplatin chemotherapy in a rat glioma model. Female F344 rats were implanted with 9L gliosarcoma tumors either intracranially or subcutaneously and treated with 1 mg/kg cisplatin injected i.p. or with 1% thalidomide in the food or with these treatments combined. Cisplatin in combination with thalidomide significantly reduced both the subcutaneous tumor volume at 30 days to 22 +/- 5% (mean +/- SEM, P < 0.001) and the intracranial tumor volume at 18 days to 44 +/- 15% (P < 0.05) of that with cisplatin alone. Thalidomide selectively increased the cisplatin concentration 10-fold in intracranial tumors (P < 0.05) and 2-fold in the subcutaneous tumors (P < 0.05) without increasing its concentration in major organs including brain and kidney. Cisplatin combined with thalidomide caused a significant decrease in vascular endothelial growth factor (VEGF) levels by 73% in intracranial tumors (P < 0.05) and by 50% in subcutaneous tumors (P < 0.05) and caused the level of active hepatic growth factor (a-HGF) to double in both the subcutaneous and intracranial tumors (P < 0.05), suggesting this treatment altered the vasculature in these tumors. We conclude the increased efficacy of cisplatin in the presence of thalidomide was due to the selective increase in cisplatin concentration within the tumors and speculate that this is the result of thalidomide or the cisplatin/thalidomide combination, selectively altering the tumor vasculature. Based on the selective effects of thalidomide on tumor cisplatin concentrations and the resulting increase in efficacy, thalidomide may also increase the efficacy of other drugs that are presently considered ineffective against glioma.

Thalidomide is currently under evaluation as an anti-angiogenic agent in cancer treatment, alone and in combination with cytotoxic agents. Thalidomide is a racemate with known pharmacologic and pharmacokinetic enantioselectivity. In a previous study with thalidomide combination chemotherapy, we found evidence of anti-tumour synergy. In this study, we examined whether the synergy involved altered pharmacokinetics of thalidomide enantiomers. Adult female F344 rats were implanted with 9L gliosarcoma tumours intracranially, subcutaneously (flank), or both. Effectiveness of oral thalidomide alone, and with intraperitoneal BCNU or cisplatin combination chemotherapy, was assessed after several weeks treatment. Presumed pseudo steady-state serum, tumour and other tissues, collected after treatment, were assayed for R- and S-thalidomide by chiral HPLC. Both serum and tissue concentrations of R-thalidomide were 40-50% greater than those of S-thalidomide. Co-administration of BCNU or cisplatin with thalidomide did not alter the concentration enantioselectivity. Poor correlation of concentration with subcutaneous anti-tumour effect was found for individual treatments, and with all treatments for intracranial tumours. The consistency of the enantiomer concentration ratios across treatments strongly suggests that the favourable antitumour outcomes from interactions between thalidomide and the cytotoxic agents BCNU and cisplatin did not have altered enantioselectivity of thalidomide pharmacokinetics as their basis.