title: Direct interstitial infusion of NK1-targeted neurotoxin into the spinal cord: a computational model.
abstract: Convection-enhanced delivery of substance P (SP) nocitoxins to the spinal cord interstitium is under consideration for the treatment of chronic pain. To characterize treatment protocols, a three-dimensional finite-element model of infusion into the human dorsal column was developed to predict the distribution of SP-diphtheria toxin fusion protein (SP-DT') within normal and target tissue. The model incorporated anisotropic convective and diffusive transport through the interstitial space, hydrolysis by peptidases, and intracellular trafficking. For constant SP-DT' infusion (0.1 microl/min), the distribution of cytotoxicity in NK1 receptor-expressing neurons was predicted to reach an asymptotic limit at 6-8 h in the transverse direction at the level of the infusion cannula tip ( approximately 60% ablation of target neurons in lamina I/II). Computations revealed that SP-DT' treatment was favored by a stable SP analog (half-life approximately 60 min), high infusate concentration (385 nM), and careful catheter placement (adjacent to target lamina I/II). Sensitivity of cytotoxic regions to NK1 receptor density and white matter protease activity was also established. These data suggest that intraparenchymal infusions can be useful for treatment of localized chronic pain.
authors.affiliation: Drug Delivery and Kinetics Resource, Div. of Bioengineering and Physical Science, ORS, NIH, Bldg. 13, Rm. 3N17, 13 South Dr., Bethesda, MD 20892-5766, USA. sarntinm@mail.nih.gov
authors.forename: Malisa
authors.initials: M
authors.lastname: Sarntinoranont
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Iadarola
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.forename: Paul F
authors.initials: PF
authors.lastname: Morrison
mesh_terms: D002908:Chronic Disease; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009498:Neurotoxins / Q000493:pharmacokinetics*; D010146:Pain / Q000188:drug therapy; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000493:pharmacokinetics*
chemical_list: D009498:Neurotoxins; D018040:Receptors, Neurokinin-1; D013373:Substance P