Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor

A potential strategy to increase the efficacy of topotecan to treat central nervous system (CNS) malignancies is modulation of the activity of ATP-binding cassette (ABC) transporters at the blood-brain and blood-cerebrospinal fluid barriers to enhance topotecan CNS penetration. This study focused on topotecan penetration into the brain extracellular fluid (ECF) and ventricular cerebrospinal fluid (CSF) in a mouse model and the effect of modulation of ABC transporters at the blood-brain and blood-cerebrospinal fluid barriers by a tyrosine kinase inhibitor (gefitinib). After 4 and 8 mg/kg topotecan i.v., the brain ECF to plasma AUC ratio of unbound topotecan lactone was 0.21 +/- 0.04 and 0.61 +/- 0.16, respectively; the ventricular CSF to plasma AUC ratio was 1.18 +/- 0.10 and 1.30 +/- 0.13, respectively. To study the effect of gefitinib on topotecan CNS penetration, 200 mg/kg gefitinib was administered orally 1 hour before 4 mg/kg topotecan i.v. The brain ECF to plasma AUC ratio of unbound topotecan lactone increased by 1.6-fold to 0.35 +/- 0.04, which was significantly different from the ratio without gefitinib (P < 0.05). The ventricular CSF to plasma AUC ratio significantly decreased to 0.98 +/- 0.05 (P < 0.05). Breast cancer resistance protein 1 (Bcrp1), an efficient topotecan transporter, was detected at the apical aspect of the choroid plexus in FVB mice. In conclusion, topotecan brain ECF penetration was lower compared with ventricular CSF penetration. Gefitinib increased topotecan brain ECF penetration but decreased the ventricular CSF penetration. These results are consistent with the possibility that expression of Bcrp1 and P-glycoprotein at the apical side of the choroid plexus facilitates an influx transport mechanism across the blood-cerebrospinal fluid barrier, resulting in high topotecan CSF penetration.     

Intravital microscopy and post mortem histology of burn shock in rabbits (author's transl)]

This paper describes results of intravital microscopic observations of the mesenteric blood and lymph vessels of the rabbit. 20% of the surface of the skin of these rabbits were burned. Immediately after producing the shock, general unspecific symptoms were seen: decrease of circulatory flow, aggregates of erythrocytes. Specific alterations consisted in leukocyte sticking, platelet aggregation, hemolysis and stasis. Vascular spasm and hemorrhage were conspicuously absent. These microcirculatory features were compared with those of different forms of shock. There was a striking similarity with the characteristics of the burn shock with the endotoxin shock. On the other hand hemorrhagic and traumatic shock exhibited similar phenomena, thus forming a second distinct group of shock as seen from a microcirculatory point. Differentiation between the groups is only possible from the specific features of microcirculation failure. These results confirm the view point, that different forms of shock evoke different pathological reactions in the terminal vascular bed.