As reported by Kent Waldrep National Paralysis Foundation at http://www.spinalvictory.org/articles/april/page03.htm
Several SCI clinical trials have been completed, and, in some cases, therapies have progressed beyond trials to the SCI patient population. Examples include Vocare and Free Hand systems, and the standard of care-a 30 mg/kg bolus of methylprednisolone (MP), a synthetic glucocorticoid, followed by 5.4 mg/kg/h over 23 h initiated within 3 h of time of injury. If initiated within 8 h from time of injury, treatment continues for 48 h. MP's mechanism of action suggested by the authors of the National Acute Spinal Cord Injury Study (NASCIS) is through inhibition of lipid peroxidation and hydrolysis that occurs at the site of the injury (Bracken et al., 1990, 1992; Bracken and Holford, 1993; Hall and Braughler, 1987; Young, 1990).
Along these lines, tirilazad mesylate, a potent lipid peroxidation inhibitor developed specifically to treat CNS trauma, with potentially fewer complications than highdose 48-h MP regimen, was tested in a randomized trial of 499 patients with 167 patients receiving 2.5 mg/kg of tirilazad mesylate or placebo given by intravenous bolus infusion over 15-20 niin every 6 h for 48 h (Bracken et al., 1997).
This study concluded that there was equivalence with 24-h MP, supporting the major role of lipid peroxidation and hydrolytic destruction of neuronal and microvascular membranes in the acute pathophysiology of SCI. Forty-eight-hour tirilazad failed to improve neurologic recovery as much as 48-h MP, suggesting an additional antiinflammatory role of MP (Bracken et al., 1997).
GM-1 (Sygen), a specific ganglioside (monosialotetrahexosylganglioside), is in open-label phase III clinical trials as a treatment strategy for chronic spinal cord injury (Fidia Phan-naceutical Corp., Italy). Gangliosides are complex acidic glycolipids present in high concentrations in the CNS cells, forming a major component of the outer leaflet of the cell's membrane bilayer.
The rationale to use GM-1 is that gangliosides stimulate growth of nerve cells and regeneration of damaged process in models of neural injury and produce positive effects on neurologic recovery in patients with stroke (Goldstein, 1995) or subarachnoid hemorrhage. SCI patients with varied lesion levels received GM-1 (18-23 doses 100 mg GM-1 sodium salt i.v., initiated within 72 h of injury; Geisler et al., 1991, 1992). There were some significant improvements in Frankel grades in the GM-1-treated groups in a 1 -year follow-up when compared to controls (n = 18; Geisler, 1998).
Promising phase I clinical trials for neurotrauma include the application of either whole body hypothermia or local cord cooling (Hansebout et al., 1984; Hayes et al., 1993; Tisherman et al., 1999;) and infusion of the fast, voltage-sensitive potassium channel blocker 4aminopyridine (4-AP; Hansebout et al., 1993; Hayes et al., 1994; Segal and Brunnemann, 1998).
Application of hypothennia either spinally or systemically is thought to provide protection for neural cells with increased secondary sensitivity to neural death and to reduce secondary inflammation, decreasing immediate mortality. Local spinal cord cooling within 81/2 h of injury in 10 patients produced a better than expected rate of recovery of sensory and motor function, and reduction in mortality rate in comparison to more traditional forms of therapy (Hansebout et al., 1984), which confirmed earlier studies with eight SCI patients treated by irrigation with 5'C saline for 2 h (Bricolo et al., 1976).
The utility of 4-AP is based on the exposure of the intemodal potassium channels that occurs as a result of demyelination, which considerably alters conduction properties in surviving demyelinated axons. Application of 4-AP blocks potassium channels and partially restores conduction properties. Phase I trials of 4-AP given in doses of 6-30 mg/kg (Hansebout et al., 1993; Hayes et al., 1994; Segal and Brunnemann, 1998) demonstrated increased motor control and sensory ability below the injury, reduction in chronic pain and spasticity, and restored voluntary bowel control in a subset patients (Hansebout et al., 1993; Hayes et al., 1994; Segal et al., 1999).
ACTIVE CLINICAL TRIALS
With the greater resolution provided by noninvasive imaging techniques such as magnetic resonance imaging (MRI), it is possible to follow the progress of material transplanted following SCI. Posttraumatic spinal cord cysts occur in approximately 5 1 % of SCI patients, with development of fluid-filled cysts that continuously expand over time, i.e., posttraumatic syringomyelia, occuring in 10% of SCI patients further jeopardizing function that was preserved after injury (Backe et al., 1991; Falci et al., 1997, 1999). Current treatment of syringomyelia consists of cord untethering and/or shunting of the syrinx (Falci et al., 1999). Animal studies demonstrate that embryonic transplants survive and integrate with host (Giovanini et al., 1997).
Phase I clinical trials are currently in progress examining intrasyrinx en bloc embryonic tissue transplants in patients with syringomyelia after SCI (Faici et al., 1997; Thompson et al., 1999; Wirth et al., 1999). The long-range goal of this approach is to provide growth factors to inhibit progressive neural cell loss that occurs in some patients, while the immediate goal is to ensure safety and feasibility of the procedure.
While preliminary results indicate that cyst obliteration is evident and that transplanted tissue did not become tumorigenic, functional improvements remain unachieved (Falci et al., 1997; Wirth et al., 1999). In addition, transplants could provide a source of both glial and neuronal cells wherein the glial cells might provide a scaffold for growing neurites, providing a cellular bridge.
Unfortunately, host neutite fibers remain within grafts and do not enter host cord due to neurite growth inhibition by the host environment. Finally, embryonic en bloc transplant can serve as a source of factors for reduction of astrocyte banier formation, and possible enhancement of conduction properties of host fibers (Zompa et al., 1997). However, data to support recovery of voluntary locomotor performance and reduction of chronic central pain syndromes after embryonic transplantation in the patient population are missing.
Additional ethical and philosophical concerns (for biomedical and health care ethics resources, see hqp://www.ethic.ubc.ca; accessed 2000 Oct. 26), transplant characterization, and infectious disease/contamination issues provide resistance to successful clinical application of this approach-transitioning support to genetically engineered, better-understood, purified cell lines (Eaton et al., 1999; Hains et al., 2000; Whittemore et al., 1997).
There is an additional phase I clinical trial in the area of transplant therapy at the University of San Paulo in which saphenous nerve grafts are used to bridge the spinal cord gap in six patients with complete spinal cord transactions (created by gunshot) performed within 6 h after injury. Over time, the peripheral nerve graphs fill the gap as demonstrated by MRI techniques but no behavioral improvement was noted (hU:Hwww.sl2inewire.com; accessed 2000 Mar 14).
In phase 11 trials are 4-AP treatment that involve about 200 patients and multiple clinics (Acorda Therapeutics, Inc.), involving incomplete chronic SCI, at least 18 months after injury, on multiple drug regimens. Outcome measures are extremely difficult in these studies using the American Spinal Injury Association (ASIA) sensory and motor scoring systems (Geisler et al., 1992) since results are extremely variable from test to test. Perhaps the easiest assessments to use are the Ashworth score (Gregson et al., 1999), the pendulum test for spasticity (Bajd and Vodovnik, 1984), and tests for bladder, bowel, and sexual function.
While results are forthcoming, it appears from early outcomes that drug administration yields significant improvement in several functions, including bowel and bladder, which may be the best and initial outcome measures to begin recovery assessments (Segal et al., 1999).
Supported ambulation studies at the University of California Los Angeles are in phase 11 clinical trials to demonstrate functional improvements. Others investigating supported ambulation include the Miami Project, the Burke Institute, and the University of Bonn (Wemig et al., 1998, 1999). In most injuries, caudal gray matter such as that in the lumbosacral cord is essentially uninjured; however, following injury, supraspinal systems do not sufficiently communicate information with cervical and lumbar elements to initiate stepping and maintain persistent locomotion.
After training with supported ambulation, adaptable circuitry can be trained to interpret complex sensory information associated with load-bearing stepping (Barbeau and Blunt, 1991; Edgerton et al., 1997a,b; Harkema et al., 1997; Wemig and Muller, 199 1; Wemig et al., 1995). As locomotion requires coordination of multisegmental connections and given intrinsic CNS plasticity, a very small biological bridge may produce a dramatic impact on locomotor function (Xu et al., 1997). Of additional relevance, cellular transplants of either mixed or pure culture offer potential for further adaptability and transfected transplants can stimulate reorganization of intrinsic and extrinsic spinal neural circuits.
Along these lines, aggressive physical therapy and/or other noninvasive therapies should be used in conjunction with invasive interventions. It is apparent that recovery of locomotion is dependent on sensory input which can "reawaken" spinal circuits and activate central pattern generators in the spinal cord, as demonstrated by spontaneous "stepping" in the lower limbs of one patient (Calancie et al., 1994, 1996).
Sensory input as would occur in aggressive physical therapy may be important, which is consistent with works by Sherrington (1910) and Grillner (1975) on mammalian locomotor neural circuits. Obstacles to aggressive physical therapy for SCI may be the health status of patients, budgetary considerations, biases despite duplicative positive scientific evidence, and lack of knowledge on the part of the physiatrists and healthcare providers.
Transplantation of activated macrophages into the spinal cord of patients with SCI is currently in phase I in Israel (Proneuron Biotechnology, U.S.A.; Weizmann Institute of Science, Rehovot, Israel). Macrophages are activated by co-incubation of the patients' harvested macrophages with myelin basic protein. Activated macrophages secrete neurotrophins, chemokines, and cytokines and actively phagocytose cellular debris.
It is hypothesized that activated macrophages will exert beneficial effects by both neurotrophic (rescues neurons) and neurotropic (stimulates neurite growth) mechanisms and through inhibition of developing reactive gliosis. Although in early stages, preliminary preclinical rodent studies demonstrate restoration of function (LazarovSpiegler et al., 1998; Rapalino et al., 1998; Schwartz et al., 1999). Despite being accepted as an Investigational New Drug (IND) by the U.S. FDA, it should be noted that no animal trials were performed in other laboratories, and replication is required prior to the application of this or any invasive procedure for clinical trials.
A largely neglected aspect of in SCI is the development of chronic pain syndromes, which occur in a majority of patients (Christensen and Hulsebosch, 1997). Within the last decade, recognition of central neuropathic pain led to the successful utilization of nonopioid analgesics such as the GABAB agonist baclofen once used exclusively in treatment of spasticity (Abel and Smith, 1994; Azouvi et al., 1996); and the anticonvulsant gabapentin (Neurotin, Parke-Davis) originally used to treat epilepsy and currently used as an analgesic for chronic central pain (Ashburn and Staats, 1999; Attal et al., 1998; Ness et al., 1998). The tricyclic antidepressant amitriptyline, shown effective in treatment of dysesthetic pain (Sandford et al., 1992), is also in phase I clinical trials in work funded by NIH. The mechanism of action by which amitriptyline produces analgesia is unclear, but may be related to inhibition of norepinephrine and serotonin reuptake (Bendtsen et al., 1996), antimuscarinc actions (Dilsaver et al., 1987), and/or strong antagonist effects at histamine Hl (Sawynok et al., 1999) and a2-adrenoreceptors (Gray et al., 1999).
There is controversy about whether the analgesia is secondary to the antidepressant effects (Bryson and Wilde, 1996; Casas et al., 1995), and the analgesic effect may depend on the noxious stimulus used (Casas et al., 1995). Oral tricyclic antidepressants are used for many chronic central pain syndromes, even those that are refractory to standard therapy including narcotics (Godfrey, 1996) so results of the amitriptyline trials seem promising.
UPCOMING CLINICAL TRIALS
Many clinical trials are in the planning stages, set to initiate as soon as this year. At Cedars-Sinai Medical Center in Los Angeles, trials that are planned involve antotransplantation of pleuripotent stem cells into SCI patients where the source of the stem cells will be the patient's own hippocampus. Along these lines, transplantation of Schwann cells into SCI patients is funded by the Myelin Project (http:Hwww.myelin.org/l 12599pr.html; accessed 2000 Oct. 26) in which the objective is to supply cells that will provide a source of myelin for the demyelinated white matter tracts.
Transplantation of porcine fetal stem cells for intractable pain and spinal cord injury (Diacrin; http:www.diacrin.com; accessed 2000 Aug 17), and AF- I and Inosine to stimulate potential sprouting of corticospinal fibers after SCI are under development (Boston Live Sciences).
Phase I clinical trials with CMIOI, an antiangiogenesis compound used in tumor reduction (Wamil et al., 1998), have been conducted by CarboMed Inc., with encouraging results and are planned in SCI. Regeneron is conducting clinical trials in partnership with Amgen using neurotrophin-3 for the treatment of constipation associated with spinal cord injury and other medical conditions.
On the horizon are delivery systems of antiapoptotic agents such as bcl-2 (Takahashi et al., 1999), antiinflammatory agents such as IL-10 (Bethea et al., 1999), acute delivery of subunit-specific excitatory amino acid receptor antagonists (Rosenberg et al., 1999; Wrathall et al., 1997), and stem cell therapy (Liu et al., 1999; McDonald et al., 1999; Zompa et al., 1997).
Remyelination of injured axons has been shown achievable in experimental animals and phase I trials with transplants of myelin-producing olfactory ensheathing glial cells are in the planning stages; however, prescreening for the optimal patient population with 4-AP to determine the patient population which would most benefit is suggested.