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Eptastigmine is a new acetylcholinesterase (AChE) inhibitor currently under development for the symptomatic treatment of Alzheimer disease. This study was conducted to establish the maximum tolerated dose and the pharmacodynamics of eptastigmine in nine healthy elderly volunteers. Subjects received single oral doses of 8 mg, 20 mg, 32 mg, and 40 mg eptastigmine and placebo according to a double-blind, randomized, rising-dose, five-way crossover design. Adverse events, blood pressure, heart rate, body temperature, forced expiratory volume, salivary flow, and pupilar activity were closely monitored during treatment. Pharmacodynamic activity of eptastigmine was evaluated with an assay of AChE activity in red blood cells. Eptastigmine doses of 8 mg, 20 mg, and 32 mg were well tolerated. Two of four subjects receiving the 40-mg dose developed profound AChE inhibition (58-59%) and reported severe adverse events (nausea, vomiting, syncope, and bradycardia), precluding further administration in the remaining subjects. Eptastigmine administration produced a weak effect on supine heart rate, body temperature, and pupil diameter. There were no effects on blood pressure, forced expiratory volume, salivary flow, and near point of focus. Acetylcholinesterase activity was inhibited in a dose-related fashion according to a sigmoidal (logistic) function. The mean (+/- SEM) maximum inhibition of AChE activity (Imax) was 14.5+/-3.3%, 20.4+/-2.3%, 28.7+/-2.9%, 45.2+/-1.3% and 53.6+/-2.9% after placebo, 8 mg, 20 mg, 32 mg, and 40 mg of eptastigmine, respectively. The theoretical maximum response (Emax) was 72.9%, and the dose that produced half of the maximum response (ED50) was 29.5 mg. At 24 hours, residual AChE inhibition ranged from 9% to 15%, with a half-life of recovery of the enzyme of approximately 10 hours. The maximum tolerated dose of eptastigmine after single-dose oral administration in healthy elderly subjects is 32 mg. Single oral doses of eptastigmine produce sustained, dose-related inhibition of AChE activity. Adverse events are related to the degree of AChE inhibition.

We have investigated the distribution, biotranformation, and excretion of streptozotocin and its 14C- and 3H-labeled metabolities in 15 patients with advanced cancer. Streptozotocin was detected in the plasma during the first 3 hours after administration while radioactive products were present for longer than 24 hours. No unchanged streptozotocin was detected in the cerebrospinal fluid (CSF); however, 14C-labeled metabolites were detected in the 2-hour CSF sample in a concentration equivalent to the 2-hour plasma level. H activity is the CSF was not detected at this time period. Radioactivity measured in biopsied tissues indicated that streptozotocin labeled with 14C and 3H or its metabolites penetrated tumor tissue. 14C tissue levels were found to approximate plasma levels; however, 3H levels were found to be greater than the corresponding plasma levels. Fifteen percent of the total dose of streptozotocin administered was recovered in the urine. 3H-labeled metabolites were recovered in excess of 60% in the urine, and approximately 30% of the 14C-labeled metabolites were recovered in the urine during a similar interval. Less than 1% of the administered 14C and 3H was recovered in the feces. 14C-labeled CO2 was also recovered, although quantitative recovery was not attained. At least three major metabolites of streptozotocin were detected in the urine by radiochromatography. Two metabolites contained only 3H and one metabolite contained both 14C and 3H in the same ratio as administered.

Patients with advanced cancer were given 5-azacytidine labeled at position 4 with radioactive carbon (14C) by either the intravenous (iv) or subcutaneous (sc) route. Absorption of the drug from the sc injection site was rapid and peak plasma levels were attained within one-half hour. Within 2 hours, the plasma level of radioactivity was approximately equal to that noted in the patients treated iv. The plasma half-life after iv injection was 3.5 hours; after sc administration, the plasma half-life was 4.2 hours. Patients receiving the drug sc excreted less drug in the urine than did those receiving the drug iv. No radioactivity was detected in the expired carbon dioxide when the drug was given by either route. Drug uptake into tumor tissue was always greater than uptake into surrounding normal tissue. The highest concentrations of radioactivity in the tissues were achieved when the drug had been given iv. Traces of radioactivity were still detectable in the tissues for as long as 6 days after administration of the drug. The incorporation of radioactivity into tumor RNA but not into DNA was demonstrated. The maximum level of radioactivity detected in the spinal fluid was equivalent to 0.2 microg of 5-azacytidine per milliliter of fluid.