Efficacy and safety study of arbaclofen placarbil in patients with spasticity due to spinal cord injury.

STUDY DESIGN: Randomized, double-blind, placebo-controlled, two-period crossover. OBJECTIVES: To evaluate the efficacy and safety of arbaclofen placarbil (AP) in patients with spasticity secondary to spinal cord injury (SCI). SETTING: United States and Canada. METHODS: Patients received extended-release AP tablets 10, 20 or 30 mg every 12 h in one of two AP/placebo sequences, with 26 days of each treatment. The primary analysis compared Ashworth scale assessments of muscle tone between AP and placebo for the muscle group with maximum baseline Ashworth score. Secondary endpoints included a patient-rated Severity of Spasticity Scale. RESULTS: In the primary analysis, AP significantly improved Ashworth scores compared with placebo over the dosing interval: least-squares mean reduction versus placebo was 0.60 for AP 20 mg (P=0.0059) and 0.88 for AP 30 mg (P=0.0007). The difference was significant for the pre-morning dose time point, 12 h after the prior evening dose, indicating that efficacy was maintained throughout the dosing interval. Treatment differences for AP 10 mg versus placebo were not significant. Severity of Spasticity ratings were significantly reduced for the combined 20/30-mg group versus placebo (P=0.018). No statistically significant differences between AP and placebo were observed for muscle strength. AP-related AEs were generally mild to moderate in intensity, and none led to early withdrawal or were serious. CONCLUSION: AP was well tolerated at all investigated dosages and, when administered at doses of 20 or 30 mg twice daily, was efficacious in reducing spasticity due to SCI.

Cervical spinal cord injury in the adult rat: assessment of forelimb dysfunction.

Traumatic injury to the adult human spinal cord most frequently occurs at the mid-to-low cervical segments and produces tetraplegia. To investigate treatments for improving upper extremity function after cervical spinal cord injury (SCI), three behavioral tests were examined for their potential usefulness in evaluating forelimb function in an adult rat model that mimics human low cervical SCI. Testing was conducted pre- and up to 4 weeks post-operation in adult female rats subjected to either contusion injury at the C7 spinal cord segment or sham-surgery. Modified Forelimb Tarlov scales revealed significant proximal and distal forelimb extension dysfunction in lesion rats at l-to-4 weeks post-cervical SCI. The Forelimb Grip Strength Test showed a significant decrease in forelimb grip strength of lesion rats throughout the 4 weeks post-cervical SCI. Significant deficits in reach and pellet retrieval by lesion rats were measured at l-to-4 weeks post-cervical SCI with the conditioned pellet retrieval Staircase Test. The results demonstrate that these qualitative and quantitative forelimb behavioral tests can be used to evaluate forelimb function following low cervical SCI and may be useful to investigate treatments for improving forelimb function in these lesions.

Dorsal spinal venous occlusion in the rat.

Occlusion of the major components of the spinal venous system is usually associated with spinal arteriovenous malformations or systemic thrombophlebitis. Although spinal venous system dysfunction has been implicated in compressive cord syndromes, myelopathies from decompression sickness, and spinal cord trauma, its pathophysiology remains unclear. To characterize disorders associated with spinal venous occlusion, we developed a model in the rat produced by focally coagulating the dorsal spinal vein transdurally at the T7 and T10 vertebral levels. Following such occlusion, venous stasis, sludging and perivascular hemorrhages in the small venous branches were observed. By 1 week postocclusion, animals developed hindlimb paralysis from which they partially recovered over time. Histologic examination in the acute phase disclosed tissue necrosis, edema, and hemorrhages predominantly in the dorsal aspect of the spinal cord. This was gradually replaced by an intense macrophagic infiltration and the partial formation of a cystic cavity by 1 month. These findings indicate that dorsal spinal vein occlusion in the rat causes significant neurologic and pathologic alterations. We conclude that this procedure produces a relevant animal model for the study of the pathophysiology of spinal venous occlusion, and it allows the characterization of its effects on spinal cord blood flow, the blood-spinal cord barrier, and the development of edema independent of cord compression. Our findings in this model provide an insight into one of the mechanisms of injury extension in spinal cord trauma and other disorders associated with spinal venous dysfunction.

Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. North American Tizanidine Study Group.

Tizanidine, an imidazoline that acts as an agonist at alpha 2-adrenergic receptors, has been shown to be effective in reducing spasticity caused by MS. This multicenter study (14 sites) assessed the efficacy and safety of oral tizanidine in patients who had spinal cord injury of > 12 months' duration. Of the 124 patients admitted to the study, 78 completed it. Tizanidine was titrated to an optimized dosage in each patient to a maximum of 36 mg/d. Muscle tone, assessed by Ashworth score, was significantly reduced (p = 0.0001) by tizanidine treatment in comparison with placebo. Video motion analysis of the pendulum test showed improvement in the tizanidine-treated patients vs placebo (p = 0.04) and showed a significant correlation with the Ashworth score (p < 0.001). No significant alterations in muscle strength or vital signs were noted in either treatment group. The most common adverse events during tizanidine treatment were somnolence, xerostomia, and fatigue. It was concluded that, overall, tizanidine is effective in reducing spasticity in patients with spinal cord injury.

Dynorphin A-induced rat spinal cord injury: evidence for excitatory amino acid involvement in a pharmacological model of ischemic spinal cord injury.

Dynorphin A reduced lumbosacral blood flow, elevated cerebrospinal fluid lactic acid concentrations and caused flaccid hindlimb paralysis and striking neuropathological changes after its injection into the spinal subarachnoid space in rats. Coadministration of the vasodilator hydralazine substantially eliminated the paralytic, anaerobic metabolic and neuropathological responses to dynorphin A. In contrast, in concentrations up to 1 mM, dynorphin A did not alter the viability of cultured rat spinal cord neurons. Thus, it appears that this peptide lacks direct neurotoxic effects and that neuronal injuries in vivo result primarily from ischemia associated with dynorphin A-induced blood flow reductions. NMDA receptor antagonists significantly improved recovery from dynorphin A-induced hindlimb paralysis, and substantially eliminated neuropathological changes without attenuating the acute blood flow reductions or lactic acid elevations. Additionally, glutamate and aspartate concentrations were increased significantly in spinal cord cerebrospinal fluid samples removed during the time that peptide-induced spinal cord blood flow reductions were observed. In contrast, neither amino acid concentration was elevated in media removed after 1-hr exposure of spinal cord neuronal cell cultures to 100 microM concentrations of dynorphin A. These results indicate that the paralysis and spinal cord injuries produced in rats after spinal subarachnoid injection of dynorphin A result predominantly from spinal cord ischemia, and further identify excitatory amino acids and N-methyl-D-aspartate receptor mechanisms as important mediators in this injury model.

Hypothermia in spinal cord injury.

Early investigations involving central nervous system (CNS) temperature lowering to protect against the detrimental effects of hypoxia and ischemia were based on the observation that hypothermia reduces brain metabolism and energy consumption. The protective effects of hypothermia have been demonstrated in numerous experimental models of cerebral ischemia and recently in models of brain trauma. These observations also led to the application of hypothermia, in the form of local spinal cord cooling (LSCC), in animal models of experimental spinal cord injury (SCI). Although some investigators have reported negative results in studies of LSCC following traumatic SCI, the majority of studies have noted beneficial effects. The favorable results in animal experimentation led to a limited number of cases where LSCC was used in the treatment of human SCI. However, results are difficult to interpret because (1) most investigators report only a small number of cases, (2) the studies lack a control population, (3) the time interval from injury to the application of cooling has been highly variable, and (4) several investigators combined drug treatments with LSCC. In these experiments, LSCC was achieved via perfusion with a cold solution or an epidural heat exchanger and the aim was to lower cord temperatures significantly (about 10 degrees C). The application of the technique itself is fraught with difficulties. It requires acute surgery in a traumatized patient, a wide multilevel laminectomy, and minimizing the time interval between injury and the application of spinal cord cooling. Recent studies in experimental brain ischemia strongly suggest that a drastic lowering of CNS temperature may be unnecessary to lessen the degree of tissue damage occurring following an ischemic brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin causes vasoconstriction, reduces blood flow and increases vascular permeability in the rat central nervous system.

Using radiolabeled microspheres, spinal cord blood flow was measured after spinal subarachnoid injections of 3.1- to 12.5-nmol doses of somatostatin through either indwelling i.t. catheters or acutely inserted intervertebral needles. With either injection technique, somatostatin caused significant dose-dependent reductions in thoracic and lumbosacral blood flow that could be partially blocked by a 5-min preinjection of the somatostatin receptor antagonist cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)], which has previously been shown to block the hindlimb flaccidity produced by these doses of somatostatin in conscious rats. The duration of these blood flow changes were appreciably less in the rats injected through indwelling i.t. catheters. Somatostatin-induced reductions in spinal cord perfusion were accompanied by transient pressor responses, reduced cardiac output, 3-fold increases in spinal cord cerebrospinal fluid lactic acid concentrations and breakdown of the blood-spinal cord barrier, as reflected by significantly increased extravasation of [125I]bovine serum albumin. By 24 hr postinjection, a 12.5-nmol dose of somatostatin caused appreciable spinal cord cellular injury, as evidenced by significant elevations in cerebrospinal fluid concentrations of lactate dehydrogenase. After topical application to exposed pial vessels of the parietal cortex, comparable doses of somatostatin caused immediate intense dose-related arteriolar vasospasm and subsequent extravasation of the visible macromolecular tracer Evans blue dye. We conclude that somatostatin has significant vasoconstrictory effects on the blood vessels of the brain and spinal cord of the rat that must be recognized and appreciated when studying its neuropharmacological actions in vivo.

Autoregulation of cerebral blood flow in patients with orthostatic hypotension after spinal cord injury.

Two groups of patients who developed orthostatic hypotension (OH) after spinal cord injury (SCI) were studied. In the first group all patients (4 females and 6 males) were asymptomatic, whereas in the second group (1 female and 9 males) all had clinical manifestations of hypotension. All but 3 patients were tetraplegic, and these patients were paraplegic above the T6 level. For this study blood pressure (BP), heart rate and cerebral blood flow (CBF) velocity were measured simultaneously on a tilt table at 0, 30, 60, and 80 degrees. Cerebral blood flow in the middle cerebral artery was measured bilaterally utilising the transcranial Doppler technique. In asymptomatic patients the mean baseline (0 degrees) BP (110 +/- 16/70 +/- 77 mm Hg systolic/diastolic) was not significantly different from the BP (106 +/- 16/68 +/- 11 mm Hg) of symptomatic patients. The mean maximal change in BP during tilting in the asymptomatic group (-23 +/- 10/10 +/- 7 mm Hg) was also not significantly different when compared to the symptomatic group (-29 +/- 13/11 +/- 6 mm Hg). CBF in the symptomatic group during the hypotensive reaction at 80 degrees was 32.5 +/- 5 cm/sec, while at the same body position in the asymptomatic group it was 40.9 +/- 8 cm/sec (significant at the p less than 0.02). In addition, CBF decreased in the symptomatic group at 80 degrees to 55.5 +/- 9.6% of baseline, while in the asymptomatic group the fall was 69.3 +/- 7.2% (p less than 0.001). Our data suggest that autoregulation of CBF rather than systemic BP plays a dominant role in the adaptation to OH in patients with SCI.

Effects of NMDA receptor antagonists following spinal ischemia in the rabbit.

Evidence has accumulated to implicate the excitatory amino acid neurotransmitters, glutamate and aspartate, in the pathophysiology of central nervous system (CNS) ischemic injury. It appears from both in vivo and in vitro experiments that they exert their excitotoxic effects in CNS ischemia by their actions at the N-methyl-D-aspartate (NMDA) receptor complex. In the present study, we examined the effects of MK-801 and ketamine, two noncompetitive NMDA receptor antagonists, in a model of spinal cord ischemia in conscious rabbits produced by occluding the infrarenal aorta for 25 min. Five minutes after reperfusion, animals were treated with either saline, ketamine, or MK-801. By 6 h postreperfusion, all treatment groups exhibited an initial recovery of hindlimb motor function, after which the saline- and ketamine-treated groups had a similar progressive deterioration in function over the next 48 h. However, the MK-801-treated rabbits continued to recover motor function such that neurological scores in these rabbits were significantly improved relative to those of the saline-treated animals at 48 h. Histopathological evaluation showed that MK-801-treated rabbits tended to have a lesser degree of central gray matter necrosis. These results indicate that MK-801 protected against the secondary deterioration associated with this model and strengthen the potential therapeutic use of NMDA receptor antagonists in the treatment of CNS ischemia.

Dynorphin A-induced rat hindlimb paralysis and spinal cord injury are not altered by the kappa opioid antagonist nor-binaltorphimine.

The selective kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) was used to distinguish a kappa opioid component in the mechanisms underlying the hindlimb paralysis, ischemia, and neuronal injury induced in the rat by the kappa opioid agonist dynorphin A. Spinal intrathecal (i.t.) injection of nor-BNI (20 nmol) either 15 min or immediately before i.t. injections of 5 or 20 nmol of dynorphin A failed to alter the dynorphin A-induced disruption of hindlimb motor function and nociceptive responsiveness. Nor-BNI also did not change the 3-fold increases in cerebrospinal fluid lactate concentrations produced by 20 nmol of dynorphin A. Neuroanatomical evaluations revealed that the cell loss, fiber degeneration, and central gray necrosis in lumbosacral spinal cords of rats treated with 20 nmol of dynorphin A were not altered by nor-BNI (20 nmol, i.t.). Thus, the spinal cord injury and associated neurological deficits resulting from i.t. injection of dynorphin A appear to be primarily, if not totally, attributable to its non-kappa opioid action(s).

Arginine8-vasopressin reduces spinal cord blood flow after spinal subarachnoid injection in rats.

Arginine8-vasopressin (AVP) causes hindlimb paralysis, loss of nociceptive responsiveness and increased arterial pressure after spinal subarachnoid injection in rats. In these experiments, the effects of paralytic intrathecal doses of AVP on rat brain and spinal cord blood flow, vascular resistance and cardiac output were measured using radiolabeled microspheres. Ten minutes after injection, AVP (10-100 pmol) elevated mean arterial pressures significantly, increased vascular resistances in thoracic and lumbosacral spinal cord and reduced blood flow to the lumbosacral spinal cord without altering cardiac output, total peripheral resistance and blood flow to brain and other spinal cord regions. Lumbosacral blood flows remained significantly reduced 30 min after injection of 100 pmol of AVP, and recovered to pretreatment base-line levels by 60 min postinjection. Lactic acid concentrations were elevated significantly in spinal cerebrospinal fluid samples removed 5 to 15 min after AVP injection (100 pmol). The selective AVP V1 receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine] arg8-vasopressin, which previously blocked the effects of AVP on hindlimb motor and nociceptive function, in these experiments also blocked the AVP-induced increases in arterial pressure and reductions in lumbosacral perfusion. Intravenous infusion of the vasodilators papaverine and nifedipine failed to block AVP-induced hindlimb paralysis. Nifedipine, however, did accelerate subsequent recovery of hindlimb motor function, although it did not alter the lumbosacral blood flow reductions measured at 10 and 30 min after AVP injection. These findings indicate that AVP has significant vascular effects in the rat spinal cord that are associated with ischemia and neurological dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular responses to intrathecal vasopressin in conscious and anesthesized rats.

Increases in mean arterial pressure and heart rate have been documented after the intrathecal administration of [Arg8]vasopressin (AVP) in rats. Prior studies in our laboratories with conscious rats indicated that these cardiovascular changes were associated with a marked hindlimb sensorimotor dysfunction. In this study, which represents the first systematic comparison of the effects of intrathecal AVP in conscious and anesthesized rats, we demonstrate that in conscious male Sprague-Dawley rats 1) the motor dysfunction induced by intrathecal AVP is accompanied by a rise in mean arterial pressure that is significantly greater than that produced by an equal intravenous dose of AVP, and 2) both paralytic and pressor effects of intrathecal but not intravenous AVP are blocked by the intrathecal administration of the V1-receptor antagonist d(CH2)5[Tyr(Me)2]AVP (V1-ANT) but are not blocked by intravenous phenoxybenzamine, hexamethonium, or [Sar1, Thr8]angiotensin II, an angiotensin II antagonist. In contrast, in anesthesized rats the arterial pressor response to intrathecal AVP was blocked by intrathecal V1-ANT, intravenous hexamethonium, and intravenous phenoxybenzamine. Furthermore, conscious but not anesthesized rats exhibited a tachyphylaxis to intrathecal AVP. These results indicate that intrathecal AVP produces both the cardiovascular changes and the sensorimotor deficits through interactions with centrally located V1-receptors. In addition, sympathetic catecholaminergic mechanisms mediate the rise in mean arterial pressure produced by intrathecal AVP in anesthesized rats, but they do not in conscious rats.

Hindlimb paralytic effects of arginine vasopressin and related peptides following spinal subarachnoid injection in the rat.

Intrathecal (IT) injection of arginine vasopressin (AVP) in rats caused a transient (less than 30 min), dose-related paralysis of the hindlimbs, loss of hindlimb and tail nociceptive responsiveness, and increased mean arterial pressure. Motor dysfunction was produced with comparable potency by lysine vasopressin (LVP) and arginine vasotocin (AVT); oxytocin (OXY) was approximately 1000 times less potent. Paralysis induced by these peptides was selectively blocked following IT pretreatment with 0.5 nmoles of the vasopressin V1 receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine] Arg8-vasopressin (d(CH2)5[Tyr(Me2)]AVP). Pressor and antinociceptive responses to AVP were also blocked by this compound. However, at higher doses (2-5 nmoles, IT), d(CH2)5[Tyr(Me2)]AVP produced hindlimb paralysis, antinociception, and pressor responses by itself. In contrast to the fiber degeneration, cell loss, and necrosis found in lumbosacral cords of rats persistently paralyzed by other peptides (dynorphin A, somatostatin, and ICI 174864), neuropathological changes were not evident in spinal cords of rats transiently paralyzed by IT AVP. These results indicate that AVP-related peptides affected diverse spinal cord functions through interactions with a V1-like receptor. The similar pattern of cardiovascular and antinociceptive responses to other peptides (dynorphin A, somatostatin, and ICI 174864), which also caused hindlimb paralysis, suggests that the former responses may actually reflect the nonselective consequences of a peptide-induced disruption of spinal cord function, rather than specific shared pharmacological effects.

TRH fails to antagonize the acute paralytic effects of intrathecal dynorphin A and substance P antagonists in the rat.

Thyrotropin releasing hormone (TRH), which has been shown to improve neurologic recovery following cervical contusive spinal injury in cats, has also recently been reported to prevent the neuronal damage produced by the intrathecal (i.t.) administration of the substance P antagonist, spantide. Spantide and other substance P antagonists share with dynorphin A (DYN A)-related peptides the ability to produce an acute hindlimb paralysis after i.t. administration in the rat. By virtue of this effect, DYN A has been implicated in the secondary injury mechanisms that follow spinal trauma. Since TRH was shown to reduce the degree of histopathological injury caused by i.t. spantide, we investigated the ability of TRH to prevent or ameliorate the acute hindlimb paralysis produced by the i.t. injection of the substance P antagonists, (D-Arg1,D-Trp7,9,Leu11)-substance P (spantide) and (D-Arg1,D-Pro2,D-Trp7,9,Leu11)-substance P, and DYN A in rats. In this study, TRH failed to improve motor function or survival following i.t. injections of substance P antagonists or DYN A.

Hindlimb paralytic effects of prodynorphin-derived peptides following spinal subarachnoid injection in rats.

Dynorphin A-(1-17) acts through non-opioid mechanisms to produce dose-related neurological deficits following injection into the lumbar spinal subarachnoid space in rats. Hindlimb motor function was examined following subarachnoid injection of dynorphin A fragments and other opioid peptides derived from prodynorphin to establish: (1) which portion(s) of the dynorphin A molecule cause hindlimb motor dysfunction, and (2) whether these paralytic actions are shared by other opioids (dynorphin B, alpha-neo-endorphin, and beta-neo-endorphin) derived from the same promolecule. To minimize the influence of enzymatic inactivation on relative bioactivities, peptides were coinjected with a combination of peptidase inhibitors previously shown to enhance the actions of dynorphin A fragments in vitro. Dynorphin A-(1-17) and -(2-17) produced dose-related neurological deficits with equal potencies and durations. Although without effect when injected alone, dynorphin A-(1-8), -(1-7) and -(3-8) caused transient motor dysfunction when co-injected with peptidase inhibitors. In contrast, dynorphin A-(1-6), -(1-5) and -(6-17) did not disrupt hindlimb motor function with or without peptidase inhibition. Dynorphin B, alpha-neo-endorphin and beta-neo-endorphin also caused hindlimb dysfunction which was potentiated by peptidase inhibition. These deficits appeared to result from non-opioid actions of these three peptides, since they were not blocked by the opioid antagonist naloxone. Thus, the paralytic effects of dynorphin A: (1) result from non-opioid actions involving the 3-7 or 3-8 positions of the molecule, and (2) are shared by other prodynorphin-derived opioid peptides.

Endogenous opioids in spinal cord injury: a critical evaluation.

Based upon evidence that opioid antagonists improve neurological outcome following either traumatic or ischemic spinal cord injury, endogenous opioids have been implicated in the pathophysiology of these disorders. Naloxone improved both spinal cord perfusion and neurological function following traumatic spinal cord injury in cats, and was subsequently observed to improve neurological outcome following ischemic spinal cord injury in rabbits. Using several opioid antagonists with varied selectivities for different types of opioid receptors, it was suggested that kappa opioid receptors are involved in both these models of spinal cord injury. In addition, spinal cord trauma in rats is associated with increased concentrations of the endogenous kappa agonist dynorphin A, and increased kappa opioid receptor binding capacity localized to the injury site. Furthermore, dynorphin A induces hindlimb and tail flaccidity following intrathecal injection in rats. Thus, the pathophysiological effects of endogenous opioids in spinal cord injury have been proposed to involve dynorphin A interactions with kappa opioid receptors. However, disparities between the actions of intrathecally injected dynorphin A in rats and the presumed actions of endogenous dynorphin A in cat and rabbit spinal cord injury have been revealed in recent experiments. Paralysis resulting from intrathecal dynorphin A is not altered by opioid receptor antagonists or TRH, produced by non-opioid dynorphin A fragments but not by other selective kappa opioid agonists, and associated with non-opioid mediated reductions in spinal cord blood flow. Furthermore, despite reports of endogenous opioid changes following rat spinal cord trauma, in contrast to cats and rabbits, naloxone failed to improve neurological outcome following traumatic rat spinal cord injury. Thus, the specific endogenous opioids and opioid receptor types involved in spinal cord injury remain to be resolved, and do not appear to be universal among different models of spinal cord injury in different species. Additionally, dynorphin A may participate in spinal cord injury mechanisms in the rat through non-opioid actions.

Amiodarone neuropathy.

Amiodarone, a drug used to treat refractory cardiac arrhythmias, produced a peripheral neuropathy in 5 of 50 cases (10%). Although the neuropathy may be severe, it tends to improve with lowering of the dosage or discontinuation of the medication.