Deborah Byrd

University of California, San Francisco

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Victor A. Levin

The University of Texas MD Anderson Cancer Center

Julia Campbell

University of Tennessee Health Science Center

Janice K. Borcich

Veterinary Medical Teaching Hospital

Richard L. Davis

École Polytechnique Fédérale de Lausanne

Judit Csejtey

Albert Einstein College of Medicine

Donald D. Giannini

Marche Polytechnic University

Branimir I. Šikić

Stanford Cancer Institute

B B Etiz

Cooperative Institutions

University of California, San Francisco

Neurological Surgery

University of California San Francisco Medical Center

The University of Texas MD Anderson Cancer Center

Stanford University

University of Tennessee Health Science Center

University of Tennessee at Knoxville

Veterinary Medical Teaching Hospital

University of California, Davis

Albert Einstein College of Medicine

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CNS toxicity and CSF pharmacokinetics of intraventricular DFMO and MGBG in beagle dogs

Cancer Chemotherapy and Pharmacology (1984)

Victor A. Levin Deborah Byrd Julia Campbell Richard L. Davis Janice K. Borcich

Beagle

Cisterna magna

Cerebral ventricle

10.1007/bf00269029

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Citations (10)

Brain, CSF, and tumor pharmacokinetics of ?-difluoromethylornithine in rats and dogs

Cancer Chemotherapy and Pharmacology (1983)

Victor A. Levin Judit Csejtey Deborah Byrd

Brain tumor

10.1007/bf00255762

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Citations (27)

Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricular 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1-nitro soureas and other nitrosoureas in beagles.

PubMed (1985)

Victor A. Levin Deborah Byrd Julia Campbell Donald D. Giannini Janice K. Borcich

The central nervous system toxicity and cerebrospinal fluid (CSF) pharmacokinetics of 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1- nitrosoureas, a (ACNU) were determined in beagles and compared to those for three other nitrosoureas, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chlorozotocin. Of the four drugs, ACNU was tolerated best and at doses of 0.2 to 0.8 mg/week for 8 consecutive weeks. We found that the average half-time for CSF elimination of ACNU was 18 min (range, 12 to 38 min). This value exceeded the known rate of ACNU decomposition in aqueous solution (28 to 29 min), implying that the disappearance of ACNU from CSF was due to hydrolytic decomposition and cellular entry and/or transcapillary loss across central nervous system capillaries. The drug exposure integral (C X t) of ACNU in the CSF after a "toxic dose low" of 0.8 mg in the dogs would achieve the equivalent of in vitro cell kills in excess of 3 logs for rat 9L and human glioma 126 cells. As a potential therapeutic agent for meningeal neoplasia, the major limiting factor may be that the CSF elimination of ACNU is rapid compared to its equilibration time from ventricle to spinal- and cerebral convexity-subarachnoid space. Based on these results, we have instituted clinical Phase I trials of intra-CSF ACNU.

Nitrosourea

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Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricularly administered bleomycin in beagles.

PubMed (1985)

Victor A. Levin Deborah Byrd Branimir I. Šikić B B Etiz Julia Campbell

The neurotoxic effects and cerebrospinal fluid (CSF) pharmacokinetics of bleomycin were evaluated in beagles after chronic intraventricular administration twice a week for 8 consecutive weeks. Bleomycin was reasonably well tolerated at doses of 0.067 to 0.3 mg/week. Doses higher than 0.3 mg/week produced marked elevation of CSF protein levels and a necrotizing vasculitis within the central nervous system. Pharmacokinetic studies were performed approximately 1 month after the completion of the toxicity studies. [3H]inulin was used as a reference compound. Both [3H]inulin and bleomycin were cleared from the CSF more slowly than in previous studies and more slowly than in normal dogs, which suggests that bulk CSF absorption was reduced by the drug, probably secondary to protein-induced blockage of the arachnoid granulations through which CSF is normally absorbed. Because a "minimally toxic" dose of bleomycin (approximately 0.1 mg/week) produces a CSF C X t of only 1.9 mg/min/ml, we believe that a Phase I clinical trial would be too dangerous given the limited therapeutic potential that a dose of 0.1 mg/week could achieve.

Clearance

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Citations (12)