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NEUROLOGY 1979;29:1280
© 1979 American Academy of Neurology

Enhancement of CNS penetration of methotrexate by hyperosmolar intracarotid mannitol or carcinomatous meningitis

Hiroshi Hasegawa, Jeffrey C. Allen, Bipin M. Mehta, William R. Shapiro and Jerome B. Posner

George C. Cotzias Laboratory of Neuro-Oncology and the Departments of Neurology (Drs. Hasegawa, Allen, Shapiro, and Posner) and Pediatrics [Dr. Allen), Memorial Sloan-Kettering Cancer Center and Cornell University Medical College; and the Laboratory of Drug Resistance and Cyto-Regulation, Sloan-Kettering Institute for Cancer Research (Dr. Mehta), New York.

Intracarotid (i.e.) hyperosmolar mannitol enhances central nervous system (CNS) penetration of intravenous (i.v.) methotrexate (MTX) in normal adult rats. A fivefold augmentation in the CSF: serum and ipsilateral brain:serum MTX concentration ratios was observed 1 hour after drug administration. Intravenous mannitol had no such effect. Rats with meningeal carcinomatosis have a partial defect in blood-brain barrier function, and the CSF: serum MTX concentration ratio was 4.6 times higher in these animals than in normal rats prior to mannitol therapy. Intracarotid hyperosmolar mannitol further augmented the blood-brain barrier permeability to intravenous MTX. Intracarotid mannitol increased the therapeutic effect of MTX, since rats with meningeal carcinomatosis that received i.v. MTX and i.e. mannitol experienced a slight enhancement in survival.

Requests for reprints should be addressed to Dr. Allen, Memorial Sloan-Kettering Cancer Center. 1275 York Avenue, New York, NY 10021.

This research was supported in part by ACS Grant No. CH 39S, NCI Grant No. CA-18856, and the Elisa-U Pardee Foundation.

Presented in part at the American Academy of Neurology, Los Angeles, April 1978.

Accepted for publication February 13, 1979.






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