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-methionyl human brain-derived neurotrophic factor (r-metHuBDNF), beagle dogs were prepared with lumbar intrathecal catheters passed through the cisternal membrane to the L1-L4 lumbar level. For kinetic studies, r-metHuBDNF was delivered by bolus or infusion through one catheter and lumbar CSF was sampled periodically through a second. As a lumbar bolus, r-metHuBDNF displayed a biphasic clearance with t(1/2)a = 0.7 hr and t(1/2)b = 7. 9 hr. Lumbar to cisternal concentrations after bolus delivery were approximately 60:1. For safety studies, dogs received continuous intrathecal infusion (2.4 ml/day) for 28 days of saline (n = 6), r-metHuBDNF at 200 (n = 6), 800 (n = 6), or 2000 (n = 7) microg/day. Control dogs showed no changes. Intrathecally infused r-metHuBDNF produced a dose-dependent increase in muscle tone and decreased coordination. Low-dose r-metHuBDNF was associated with moderate increases in muscle tone after 22-28 days of infusion. No clinically important changes were noted in rectal temperature, arterial pressure, respiration and heart rate, body weight, food consumption, stool or urine output, or change in blood chemistries measured throughout the study. Cisternal CSF protein and glucose sampled at 28 days were not different between dose groups and all cultures were negative. Histopathological examination of the spinal cord typically revealed some degree of chronic inflammation around the catheter, including fibrotic adhesions and focal accumulations of lymphoid and plasma cells, but these effects were not dose dependent. In other dogs receiving r-metHuBDNF (2000 or 4000 microg/day), termination of infusion resulted in significant recovery.
Yaksh
T L
TL
Department of Anesthesiology, University of California, San Diego, California, 92903, USA.
Rathbun
M L
ML
Dragani
J C
JC
Malkmus
S
S
Bourdeau
A R
AR
Richter
P
P
Powell
H
H
Myers
R R
RR
Lebel
C P
CP
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb; D006801:Humans; D007263:Infusions, Parenteral; D007444:Inulin / Q000008:administration & dosage / Q000134:cerebrospinal fluid; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects; D011897:Random Allocation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000633:toxicity; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D019208:Brain-Derived Neurotrophic Factor; D011994:Recombinant Proteins; C109458:r-metHuBDNF protein, recombinant; D007444:Inulin