The Phosphodiesterase-4 Inhibitor, Rolipram, Decreases Progressive Tissue Pathology in a Porcine Model of Contusive Spinal Cord Injury

Proceedings of the NASS 25th Annual Meeting / The Spine Journal 10 (2010) 1S–149S

Electronic Posters P1. Evaluation of an rhBMP-2 Formulation in 2-level Posterolateral Lumbar Spine Arthrodesis Edward P. Abraham, MD1, John Hurlbert, MD2, David Alexander, MD3, Stewart Bailey, MD4, Charles Fisher, MD5; 1Atlantic Health Sciences Corporation, Saint John Campus, Dalhousie University, Saint John, NB, Canada; 2Foothills Medical Center, Calgary, AB, Canada; 3Halifax Infirmary, Halifax, NS, Canada; 4Victoria Hospital, London, ON, Canada; 5 Vancouver General Hospital, Vancouver, BC, Canada BACKGROUND CONTEXT: Spine surgeons recognize the challenging fusion environment in lumbar posterolateral arthrodesis procedures. Iliac crest bone graft (ICBG) as a gold standard is associated with an unacceptably high rate of pseudarthrosis. While there are studies reporting successful use of bone morphogenic proteins in single level lumbar posterolateral fusion (PLF), little is known on their benefit in multilevel cases. PURPOSE: The purpose of this study was to compare the clinical and radiological outcomes of instrumented two-level fusions using an rhBMP-2/ BCP formulation versus ICBG at a minimum follow-up of 4 years. In this formulation rhBMP-2 was at a concentration of 2 mg/cc in a Biphasic Calcium Phosphate (BCP, 60% hydroxyapatite/40% tricalcium phosphate) ceramic granule carrier (Medtronic,Memphis,TN). STUDY DESIGN/SETTING: This is a multicentered, prospective RCCT where patients undergoing 2-level PLF’s received either autologous ICBG or 30 cc of rhBMP-2/BCP. Clinical and radiological evaluations were performed preoperatively and postoperatively at 1.5, 3, 6, 12, 24 and 48 months including Oswestry Disability Index(ODI), SF-36, VAS back and leg pain questionnaires. Plain radiographs and thin slice CAT scans were independently assessed at 6, 12, 24, and 48 months. Fusion criteria included bilateral bridging trabecular bone at each level, less than 3 mm translation and less than 5 degrees angulation on motion studies. PATIENT SAMPLE: Twenty-nine patients were enrolled and randomized to 2 groups: Control - Those receiving ICBG, and Study - Those receiving rhBMP-2/BCP alone. OUTCOME MEASURES: Clinical outcome measures consisted of ODI, SF-36 and VAS scores. Radiological outcome measures consisted of plain radiographs with motion analysis and thin slice CAT. Evaluations were carried out to 4 years minimum follow-up for all 29 patients. METHODS: Twenty-nine patients requiring 2 level PLF were enrolled in this multicentered, prospective, controlled clinical trial. 30 cc of rhBMP-2/ BCP or autologous ICBG was used as the fusion substrate. Preoperative and postoperative (1.5, 3, 6, 12, 24, and 48 mo) clinical and radiological evaluations were carried out consisting of ODI, SF-36, VAS back and leg pain scores as well as radiographs and CAT assessment. RESULTS: Seventeen patients received ICBG alone(control) and twelve received the 30 cc rhBMP-2/BCP formulation(study). With the use of rhBMP-2/BCP, average OR time was reduced 3.8 to 2.9 hrs and average blood loss was reduced from 1070 to 870 ml. All 29 pts (100%) reached 48 month follow-up. Clinical improvements were similar in both groups. Fusion success, as determined by strict criteria, was improved with rhBMP-2/BCP (90%) compared to ICBG (58%). CONCLUSIONS: These results indicate that attempting lumbar PLF with rhBMP-2/BCP may yield improved arthrodesis success in challenging twolevel procedures. In addition OR time and Blood Loss were reduced and donor site pain eliminated in the study group. FDA DEVICE/DRUG STATUS: rhBMP-2/BCP: Investigational/Not approved. doi: 10.1016/j.spinee.2010.07.277 P2. The Phosphodiesterase-4 Inhibitor, Rolipram, Decreases Progressive Tissue Pathology in a Porcine Model of Contusive Spinal Cord Injury Cheng-Chih Liao, MD1, Juan P. Solano, MD2, Howard B. Levene, MD, PhD2, Kyle R. Padgett, PhD2, Michael A. Nares, MD2, Manny Gonzalez-

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Brito, DO , Damien D. Pearse, PhD ; Chang Gung University and Hospital, Kweishan, Touyuon, Taiwan; 2University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA; 3Miami Project to Cure Paralysis, Miami, FL, USA BACKGROUND CONTEXT: Spinal cord injury (SCI) is a debilitating condition due to limitations in the ability of the injured CNS to mediate meaningful self-repair. We have previously reported that the delivery of the phosphodiesterase-4 inhibitor, Rolipram, to SCI rats can provide neuroprotection, enhance axon growth and remyelination as well as improve functional outcome. Rolipram being a drug that has already been used in people for depression, therefore has clinical potential as a therapy for SCI. PURPOSE: In light of significant differences in physiology and anatomy between rodents and man as well as importance of employing clinically relevant experimental SCI models, we sought to investigate the safety, toxicity, adverse behavioral effects and protective efficacy of Rolipram in a larger animal model of contusive SCI, the Yuccataan micropig. Obtaining such data is important before initiation of clinical studies in human SCI. STUDY DESIGN/SETTING: This is a pre-clinical animal study. PATIENT SAMPLE: Ten pigs weighing 15 kg were randomly assigned into two groups (5 per group), receiving either Rolipram or saline control infusion. OUTCOME MEASURES: Behavioral responses (activity, emesis) to agent administration were monitored daily in the animals during the infusion period. Serial serological studies were performed every other day to determine agent toxicity. T2 weighted MRI of the contused spinal cord was performed within 2 hours of injury and at weekly intervals to compare the temporal evolution of injury among treatment groups. The area encompassing a hyperintense T2 MRI signal was noted in each scan to compile for each animal the total volume of tissue injury. Two weeks following SCI, animals were perfused with 4% paraformaldehyde and the CNS as well as vital organs (liver, kidneys, heart, spleen, and lymph nodes) were harvested for histopathological evaluation. METHODS: After successful endotracheal general anesthesia (GA) and T7 laminectomy, contusive SCI was induced using a modified pneumatic cortical contusion impactor to the exposed thoracic cord. At 4 hours post-SCI, animals received either i.v. Rolipram (1 mg/kg in 20 ml 15% EtOH: saline vehicle) or 20 ml saline with a slow infusion rate of two hours. An anti-emetic agent, ondansetron (0.15 mg/kg, i.v.), was given to animal 30 minutes prior to each infusion. Mean arterial pressure (MAP) of the animals was recorded under GA during the first infusion postSCI. For the following 14 days, same regimen was repeated daily without anesthesia. A linear regression was used to analyze the change of MAP during agent infusion and nonparametric analysis used to compare the serological and radiological outcomes between groups. RESULTS: In animals receiving i.v. Rolipram, tremor, teeth grinding, irritability, loss of appetite and foamy salivation was observed during the first hour of infusion. These reactions were not observed in saline controls or at later times post-infusion in Rolipram-treated pigs. In uninjured animals only loss of appetite and salivation were seen. Pre-treatment with i.v. ondansetron (0.15 mg/Kg) and a slow infusion rate prevented the known emetic effect of Rolipram. Compared the initial MRI injury volumes 2 h post-SCI, pigs receiving Rolipram had significantly smaller percentages of injury volume expansion on ex-vivo MRI than saline (124.4% vs. 154.3%, respectively, p50.0286). Rolipram (i.v.) significantly decreased MAP up to 45% in the first 15 minutes of infusion under GA (slope5-3.14, r250.81). Decreasing the dose of inhalation anesthetic agent could reverse the hypotensive effect of i.v. Rolipram. This effect did not occur in uninjured Rolipram treated control. There were no out-of-normal-range effects of Rolipram on serological or histological outcomes between two groups. CONCLUSIONS: Rolipram (1 mg/kg, i.v.) may be safely given after SCI. Rolipram decreases progressive tissue pathology following SCI in this larger clinical-relevant animal model. It will be necessary to prevent i.v. Rolipram-induced hypotension in future human SCI clinical studies. FDA DEVICE/DRUG STATUS: Rolipram: Investigational/Not approved. doi: 10.1016/j.spinee.2010.07.278

All referenced figures and tables will be available at the Annual Meeting and will be included with the post-meeting online content.