R. E. Watson1, J. Yee1, P. Franklin1, T. Beck1, R. Nagata2
1. Safety Assessment, SNBL USA, Everett, WA, United States.
2. SNBL Japan, Kagoshima, Japan.
Physostigmine is a cholinesterase inhibitor commonly used in behavioral pharmacology research. Physostigmine reversibly binds to acetylcholinesterase, increasing acetycholine in the neuromuscular junction and stimulating nicotinic and muscarinic receptors. Various cholinesterease inhibitors have shown promise in treating Alzheimer’s disease, various ocular disorders, Parkinson’s and schizophrenia, and phystostigmine is a useful positive control in studies performed to assess these and other potential drugs. To characterize the effects of physostigmine (Trade name Eserine, Sigma-Aldrich®) in cynomolgus monkeys (Macaca fascicularis), a common primate research model, female monkeys (n=4 per group; 6 to 8 years of age and 3.3 to 5.7 kg) were intravenously (IV) dosed with either saline or physostigmine at doses of 0.02, 0.04 and 0.08 mg/kg, on Days 1, 3, and 5. Assessments included clinical observations taken 1 min, 15 min, and 30 min postdose; weekly body weights; urinalysis (Days -4, 8, and 11); clinical pathology parameters (Day -4; 0.5 hr. postdose on Days 1, 3, 5; Days 8 and 11); and standard necropsy/histopathology. Serum cholinesterase was assessed on Day -4; 0.25 and 0.5 hours postdose on Days 1, 3, and 5; and on Days 8 and 11. Transient clinical signs consistent with cholinesterase inhibition, including salivation, lacrimation, diarrhea, vomiting and shaking, were seen at all doses within 30 minutes postdose, and were most pronounced on Day 5 with 0.08 mg/kg IV. Cholinesterase decreased in a dose-dependent manner, peaking at the Day 5, 15 minutes postdose. Mean glucose levels increased on Days 1, 3, and 5, and may be a physiological response related to enhanced catecholamine release. Cholinesterase and glucose levels returned to baseline on Day 8. Collectively these data indicate that physostigmine has predictable, reversible effects in the monkeys, and was generally well tolerated under the escalating dose regimen employed. This provides data supporting the use of physostigmine as a control for CNS studies performed in a contract research organization setting.