gastrointestinal tract. 12 , 14 This information is integrated with taste sensory afferents in the nucleus tractus solitarius. 14 Mechanical and chemical stimulation of the gastrointestinal tract and humoral signals released on nutrient stimulation conveyed by vagal afferents converge on the nucleus tractus solitarius to induce satiety. 4 , 5 , 9 The findings in this patient support the previous data from animal models regarding the importance of brainstem control of satiety pathways in humans. Tumor-induced dysfunction of afferent and/or efferent pathways and caudal
Debbie K. Song and Russell R. Lonser
Marc R. Mayberg
compounds has not yielded an effective therapeutic vasodilator. The reasons for this situation are many and have been enumerated elsewhere. First, there may be structural changes in the artery wall, which prevent dilation. 13–15 T his m ay explain t he efficacy of m echanical dilation by angioplasty in vasospasm 7 , 11 , 17 and the longer persistence of dilation by angioplasty compared with intraarterial papaverine. 6 Second, there have been a number of animal models of vasospasm, 16 but most do not fully recapitulate the time course, severity, and associated clinical
Prashant Chittiboina, John D. Heiss, Katherine E. Warren and Russell R. Lonser
W hile the properties of convective delivery have been defined in naïve nervous system tissue of small and large animal models, 3 , 4 , 10 , 11 , 18 , 19 , 21 , 27 , 33 the properties of convection-enhanced delivery (CED) under the pathological conditions encountered in human clinical applications are not understood. Insight into convective properties in clinical circumstances will be critical to successfully applying convective drug delivery to the treatment of currently untreatable neurological disorders and to developing predictive modeling paradigms
Paul F. Morrison, Russell R. Lonser and Edward H. Oldfield
subsequently, no clinical benefit was observed and this delivery route was abandoned. To overcome these limitations, GDNF, or a viral vector expressing GDNF, was distributed in the striatum using CED and was found to reverse parkinsonian symptoms in animal models of PD, 13 , 17 which led to clinical trials in which GDNF was distributed in the putamen via CED. Unlike intraventricular delivery and other methods that rely on diffusion for distribution, CED is not limited by an agent's molecular weight, concentration, or restricted diffusive properties. 7 , 25 Convection
Russell R. Lonser, Malisa Sarntinoranont, Paul F. Morrison and Edward H. Oldfield
B ased on the rapid progression in understanding the precise pathobiology underlying various neurological diseases, a number of promising new putative therapeutics have been developed for specific disorders that have been ineffectually treated or are not currently treatable. While these agents have been successful in reversing disease-related pathology in vitro and/or in animal models, they have not been successfully translated into clinically effective therapies. One of the largest obstacles to the successful conversion of putative therapeutics into
J. David Wood, Russell R. Lonser, Nitin Gogate, Paul F. Morrison and Edward H. Oldfield
investigate the potential use of direct convective delivery in the spinal cord of a common animal model, we examined the feasibility and parameters of convective delivery into the nontraumatized and traumatized rat spinal cord. Materials and Methods Animal Preparation Eighteen male Sprague—Dawley rats weighing between 275 and 375 g were used in this experiment. Chloral hydrate (4 mg/kg) was injected intraperitoneally to induce and maintain anesthesia throughout the procedures. Body temperature was maintained, via heating pad, at 37 to 38°C. All animal investigations
Michael Y. Chen, Russell R. Lonser, Paul F. Morrison, Lance S. Governale and Edward H. Oldfield
Object. Although recent studies have shown that convection can be used to distribute macromolecules within the central nervous system (CNS) in a homogeneous, targeted fashion over clinically significant volumes and that the volume of infusion and target location (gray as opposed to white matter) influence distribution, little is known about other factors that may influence optimum use of convection-enhanced distribution. To understand the variables that affect convective delivery more fully, we examined the rate of infusion, delivery cannula size, concentration of infusate, and preinfusion sealing time.
Methods. The authors used convection to deliver 4 µl of 14C-albumin to the striatum of 40 rats. The effect of the rate of infusion (0.1, 0.5, 1, and 5 µl/minute), cannula size (32, 28, and 22 gauge), concentration of infusate (100%, 50%, and 25%), and preinfusion sealing time (0 and 70 minutes) on convective delivery was examined using quantitative autoradiography, National Institutes of Health image analysis software, scintillation analysis, and histological analysis.
Higher rates of infusion (1 and 5 µl/minute) caused significantly (p < 0.05) more leakback of infusate (22.7 ± 11.7% and 30.3 ± 7.8% [mean ± standard deviation], respectively) compared with lower rates (0.1 µl/minute [4 ± 3.6%] and 0.5 µl/minute [5.2 µ 3.6%]). Recovery of infusate was significantly (p < 0.05) higher at the infusion rate of 0.1 µl/minute (95.1 ± 2.8%) compared with higher rates (85.2 ± 4%). The use of large cannulae (28 and 22 gauge) produced significantly (p < 0.05) more leakback (35.7 ± 8.1% and 21.1 ± 7.5%, respectively) than the smaller cannula (32 gauge [5.2 ± 3.6%]). Varying the concentration of the infusate and the preinfusion sealing time did not alter the volume of distribution, regional distribution, or infusate recovery.
Conclusions. Rate of infusion and cannula size can significantly affect convective distribution of molecules, whereas preinfusion sealing time and variations in infusate concentration have no effect in this small animal model. Understanding the parameters that influence convective delivery within the CNS can be used to enhance delivery of potentially therapeutic agents in an experimental setting and to indicate the variables that will need to be considered for optimum use of this approach for drug delivery in the clinical setting.
Ali Reza Fathi, Ryszard M. Pluta, Kamran D. Bakhtian, Meng Qi and Russell R. Lonser
vasculature. 20 However, whether NaNO 2 is acting selectively on spastic intracranial vessels must be further confirmed in patients with SAH in future studies. Potential Study Limitations While the current study data provide direct insight into the potential therapeutic effects of NaNO 2 , there are potential limitations of this animal model of SAH. Animal models do not reflect the entire clinical condition of patients with aneurysmal SAH. Cardiac dysfunction, hydrocephalus, and increased intracranial pressure, which can occur in patients with SAH, are not reflected
Jeffrey W. Degen, Stuart Walbridge, Alexander O. Vortmeyer, Edward H. Oldfield and Russell R. Lonser
application of an animal model. J Neurol 224 : 183 – 192 , 1981 Weizsaecker M, Deen DF, Rosenblum ML, et al: The 9L rat brain tumor: description and application of an animal model. J Neurol 224: 183–192, 1981 31. Wolff JE , Trilling T , Molenkamp G , et al : Chemosensitivity of glioma cells in vitro: a meta analysis. J Cancer Res Clin Oncol 125 : 481 – 486 , 1999 Wolff JE, Trilling T, Molenkamp G, et al: Chemosensitivity of glioma cells in vitro: a meta analysis. J Cancer Res Clin Oncol 125: 481–486, 1999
Russell R. Lonser, Robert J. Weil, Paul F. Morrison, Lance S. Governale and Edward H. Oldfield
Moreover, the properties of convection allow for regional delivery of large molecular weight compounds in a homogeneous, targeted, reproducible, and safe manner. 5, 6, 8 These features indicate that convective delivery might be an excellent method for intraneural drug delivery. To determine if this approach can be used to enhance the delivery and distribution of macromolecules into the peripheral nervous system, we examined delivery of macromolecules by convection into the tibial nerves of primates. Materials and Methods Animal Model Five adult primates (Macaca