Drug development in spinal cord injury: What is the FDA looking for?

Abstract

Abstract-It has long been recognized that much of the posttraumatic degeneration of the spinal cord following injury is caused by a secondary injury process that occurs during the first minutes, hours, and days after spinal cord injury (SCI). A key biochemical event in that process is reactive oxygen-induced lipid peroxidation (LP). Indeed, the administration of a high-dose regimen of the glucocorticoid steroid methylprednisolone (MP) has been shown to inhibit post-traumatic LP in animal models of SCI, and to improve neurological recovery in spinal cord-injured humans. This resulted in the registration of high-dose MP for acute SCI in several countries, although not in the U.S. Nevertheless, this treatment quickly became the standard of care for acute SCI, since it was already on the U.S. market for many other indications. Subsequently, it was demonstrated that the nonglucocorticoid 21-aminosteroid tirilazad could duplicate the antioxidant neuroprotective efficacy of MP in SCI models, and evidence of human efficacy has been obtained. This article explains the process of the discovery, development, and Food and Drug Administration regulation of new drugs for SCI; reviews the past development of MP and tirilazad for acute SCI; identifies the regulatory complications involved in future SCI drug development; and suggests some promising therapeutic approaches that could either replace or be added to high-dose MP.

Effects of andrographolide and 14-deoxy-11,12-didehydroandrographolide on cultured primary astrocytes and PC12 cells

“…After trauma, this process is initiated by reactive oxygen species (ROS) and injures parenchymal cell membranes (Hall and Braughler, 1989). High doses of the glucocorticoid steroid methylprednisolone (MP) have been shown to inhibit post-traumatic LP in animal models of SCI and improve neurological recovery in humans with SCI (Hall, 2003). Therefore, control of ROS generation is another promising drug target for CNS regeneration and SCI.…”

“…However, these actions also cause further inflammation and additional damage (Fitch et al, 1999). Free radicals and oxidative species generated by macrophages result in lipid peroxidation-mediated cell death (Hall, 2003). High doses of methylprednisolone (MP) that reduce reactive oxygen-induced lipid peroxidation have been used for treating SCI (Genovese et al, 2006;Hall, 2003).…”

“…Free radicals and oxidative species generated by macrophages result in lipid peroxidation-mediated cell death (Hall, 2003). High doses of methylprednisolone (MP) that reduce reactive oxygen-induced lipid peroxidation have been used for treating SCI (Genovese et al, 2006;Hall, 2003). Administration of antiinflammatory drugs to inhibit secondary degenerative reactions after SCI results in improved locomotion and reduced histopathological changes (Genovese et al, 2006;Koopmans et al, 2009;Lee et al, 2003;Mulcahy et al, 2003;Nesic et al, 2001).…”

Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue

“…Currently, no FDA-approved drug exists for the treatment of acute SCI. Methylprednisolone, has been widely used, albeit off-label, in the care of acute SCI with limited efficacy and remains a controversial therapeutic that has yet to garner FDA approval [2][3][4][5][6] . An estimated 150,000-200,000 worldwide cases of spinal cord injury (SCI) are diagnosed annually, with some 2.5 million people living chronically with paralysis secondary to SCI.…”

Activated autologous macrophage implantation in a large-animal model of spinal cord injury

“…Despite the rapid progression of AAM implantation therapy for SCI from the laboratory to evaluation in the clinical setting, accepted pharmacological practice suggests that human trials should be based on reproducible animal experiments that demonstrate safety in at least 2 different species, and, ideally, efficacy in a nonrodent species. 10 Consequently, we sought to replicate the results obtained by Rapalino et al 29 by using a similar protocol of AAM implantation in a canine model of SCI. Ethical and medical support concerns at our institution pertaining to induction of paraplegia in large animals necessitated a hemisection as opposed to a complete transection model.…”