**Acknowledgements**

Alanine aminotransferase (ALT) in males, and γ-glutamyl transferase (GGT), and alkaline phosphatase in females were minimally to mildly elevated in the 300 mg/kg group on Day-2. All of these findings on Day-2 resolved by Day-15. Transient elevations in transaminases were

of toxicity (other than hepatic cysts) was noted at autopsies, including CNS. Table 7 compares

A single IV dose administration study was performed in adult beagle dogs employing single doses (10 – 30 mg/kg) of **1**. No treatment related fatalities occurred. Numerous clinical signs reflecting treatment-related effects were noted in both sexes of all groups. Pertinent clinical signs noted included decreased activity, autonomic hyperactivity – vomiting, decreased urination, salivation, and lacrimation. The effects were of immediate onset (within one hour post dose), with most of the signs clearing by Day-2 of the study. However, decreased activity persisted for Days 2, 3, and 4 in some of the animals and through the remainder of the study. Slight body weight losses noted in some animals were not dose-dependent and it could have been attributable to the clinical signs (and associated stress) caused by the vehicle. There were marked elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and sorbitol dehydrogenase (SDH) noted in controls and all treated groups and apparently attributable to the vehicle – a Klugel/Tween mixture that will not be used in the clinical studies. All liver functions reversed by Day-15. This acute and transient effect on liver enzymes exhibited no dose-dependent pattern and was also apparently attributable to the vehicle. The

No hematological deficiencies were noted in any group. Drug-related neurotoxicity was not observed. This was confirmed by second opinion (RT), who conducted silver stains and confirmed MPI's observation that there were no microscopic pathological CNS changes

Based on the conditions and findings of this study, a single bolus intravenous injection of **1** to groups of beagle dogs at dose levels of 10, 20 and 30 mg/kg produced no effects that were directly related to the test article; instead they were probably attributable to the 0.3% Klucel

Pharmacokinetic studies were conducted in two species – rats and dogs. Parameters were obtained from Gauss Newton algorithm modeling [3]. The values are compared in Table 6. No statistical differences between male and female rats were noticed. The differences in half life can be explained in reference to administration routes – dog-IV bolus *vs*. rat – IV infusion over 3 hrs. Similarly, the clearance is higher in the bolus studies as expected with a surge of drug

In the learning/cognitive screening study, rats treated with **3** took a longer period of time to find the pedestal *vs*. **1**, **2** and the controls. Despite normal gross appearance of the rats after 7 hr (Table 4), the **3** treated animals demonstrated impaired learning (Table 5). There were no signs of learning impairment noted in the rats treated with **1** or **2**, as was seen for **3**. **2** is a polychlorinated 4-hydroxypyridine (Fig. 1) and exists as a zwitterion that is too polar to cross the BBB. This behavior has been observed for other 4-hydroxypyridines [20]. The water

to hepatic clearance of the drug. Neither gross nor microscopic evidence

considered to be 2o

calculated starting therapeutic doses for humans [19].

258 Tumors of the Central Nervous System – Primary and Secondary

latter finding was not observed in the rat study.

present in the brains of dogs treated with **1** [19].

+1.92% Tween® 80 vehicle used.

being filtered.

Supported by NCI/SBIR grants – 5R44CA85021 and 1R43CA132257
