The Central Nervous System has often been classified as a "
drug sanctuary" as most anticancer drugs do not achieve effective penetration of the blood-brain barrier. With more effective systemic
chemotherapy programs (especially in acute
leukemia in children), the incidence of
meningeal tumor involvement has increased. Even though a number of systemically administered agents might be used in treating the CNS, only three have been used intrathecally with good clinical results: the
antimetabolites methotrexate (MTX) and
cytosine arabinoside (
Ara-C) and the alkylating derivative thiophosphoramide (
thio-TEPA).
Drug distribution in the CSF which is injected by lumbar puncture does not generally allow for delivery of effective quantities of
drug to the cisternae nor the ventricles. Thus direct
intraventricular injection via a subcutaneously implanted (Ommaya) reservoir is necessary to achieve adequate
drug levels in the higher CNS cavities. The peak ventricular concentration of MTX, which was administered by Ommaya reservoir, at a dose of 15mg/m2, was 2.5 +/- 0.9 X 10(-4)M, and remained as a level of 10(-6)M for 72 hours with a half-life of 10.5 hours. During an intravenous 6 hour-infusion at a dose of 750-3,000mg/m2, MTX concentration in CSF reached 8.2 X 10(-7)M to 2.7 X 10(-6)M. The
drug content in CSF had a linear concentration related to the
drug level in plasma. Intrathecal MTX and
Ara-C frequently cause symptoms of meningeal irritation. Occasionally cases of weakness and
paralysis and rare instances of severe
encephalopathy may occur. The best established causes of these symptoms is high concentration of these drugs in the CSF, or prolonged exposure of the brain to low CSF concentration.(ABSTRACT TRUNCATED AT 250 WORDS)