Safety and Pharmacokinetics of 4-Aminopyridine Derivatives in Dogs
ACVIM 2008
N.J. Olby1; J.W. Humphrey1; M. Papich1; N. Parke1; K. Spinapolis1; P.M. Mehta1; T. Harris1; R. Shi2; D. Smith2
1North Carolina State University, Raleigh, NC, USA; 2Purdue University, West Lafayette, IN, USA

The myelin sheath is critical for secure axonal conduction but demyelination is a consequence of many different pathological processes within the nervous system. Loss of myelin can lead to leakage of potassium from exposed potassium channels in the axonal membrane, blocking axonal conduction and producing neurological deficits. 4-Aminopyridine (4-AP) is a potassium channel blocker that restores conduction to demyelinated axons and has been shown to improve neurological function following spinal cord injury. However, it produces unwanted side effects such as tremors and seizures at doses close to the effective dose. In order to develop safer and more effective alternatives to 4-AP, derivatives have been tested in in vitro and in vivo models of spinal cord injury in guinea pigs. Three drugs showed promise as therapeutic agents--methyl-, ethyl- and n-(4-pyridyl)-t-butyl-carbamate derivatives (MC, EC and t-BC). The aims of this study were to determine the safe range of doses of these drugs in dogs and to evaluate their pharmacokinetic properties.

Normal beagle dogs aged between six and 18 months were used. A complete blood cell count and serum biochemistry panel were performed prior to and 24 hours after drug administration. Each dog had a jugular catheter placed to facilitate blood sampling at regular intervals for the pharmacokinetic studies. Blood samples were heparinized at the time of sampling and stored for drug concentration measurements using high performance liquid chromatography (HPLC). Following drug administration, vital parameters and behavior were recorded hourly for six hours, then at lower frequencies for the subsequent 18 hours. Drugs were administered to two dogs at a time at doses extrapolated from the work in guinea pigs; on each subsequent testing session the dose was doubled until either adverse effects were noted or the dose exceeded the effective dose.

None of the drugs produced adverse effects in any of the dogs at any of the doses evaluated. HPLC measurement of plasma levels showed that the MC and EC derivatives were very similar to 4-AP in their absorption and elimination. The MC derivative was administered at doses of 0.5 to 6mg/kg and the EC derivative was administered at doses of 0.5 to 2 mg/kg. Peak blood levels were reached within one to three hours and there was little detectable drug remaining by 24 hours after administration. The t-BC derivative was far more potent than the other compounds when tested in vitro and so was administered at doses ranging from 0.015mg/kg to 0.15mg/kg. It was absorbed rapidly reaching peak levels within 30 to 60 minutes of administration. In all three drugs, plasma concentrations higher than those that restored conduction in vitro were achieved without causing adverse effects. We conclude that these derivatives are safe alternatives to 4-AP and phase 1 clinical trials are warranted. The lack of adverse effects may reflect poor penetration of the blood brain barrier and so measurement of CSF levels is indicated.

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Natasha Olby


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