Kinetic and Safety Studies on Intrathecally Infused Recombinant-Methionyl Human Brain-Derived Neurotrophic Factor in Dogs

To define the kinetics and safety of spinally infused recombinant-methionylhuman brain-derived neurotrophic factor (r metHuBDNF), beagledogs were prepared with lumbar intrathecal catheters passedthrough the cisternal membrane to the L1-L4 lumbar level. Forkinetic studies, r-metHuBDNF was delivered by bolus or infusionthrough one catheter and lumbar CSF was sampled periodicallythrough a second. As a lumbar boles, r-metHuBDNF displayed abiphasic clearance with ta = 0.7 hr and tb = 7.9 hr. Lumbarto cisternal concentrations after bolus delivery were approximately60:1. For safety studies, dogs received continuous intrathecalinfusion (2.4 ml/day) for 28 days of saline (n = 6), r-metHuBDNFat 200 (n = 6), 800 (n = 6), or 2000 (n = 7) µg/day. Controldogs showed no changes. Intrathecally infused r-metHuBDNF produceda dose-dependent increase in muscle tone and decreased coordination.Low-dose r-metHuBDNF was associated with moderate increasesin muscle tone after 22–28 days of infusion. No clinicallyimportant changes were noted in rectal temperature, arterialpressure, respiration and heart rate, body weight, food consumption,stool or urine output, or change in blood chemistries measuredthroughout the study. Cisternal CSF protein and glucose sampledat 28 days were not different between dose groups and all cultureswere negative. Histopathological examination of the spinal cordtypically revealed some degree of chronic inflammation aroundthe catheter, including fibrotic adhesions and focal accumulationsof lymphoid and plasma cells, but these effects were not dosedependent. In other dogs receiving r-metHuBDNF (2000 or 4000µg/day), termination of infusion resulted in significantrecovery.