Sherry R. Brunnemann

Safety and Efficacy of 4‐Aminopyridine in Humans with Spinal Cord Injury: A Long‐Term, Controlled Trial

Study Objective. To determine the effects of the long‐term administration of 4‐aminopyridine (4‐AP) on sensorimotor function in humans with longstanding spinal cord injury (SCI).

Circulating levels of IL-2R, ICAM-1, and IL-6 in spinal cord injuries☆☆☆

OBJECTIVE To measure circulating levels of well-studied, easily quantifiable surrogate markers or mediators of inflammation and tissue remodeling in patients with spinal cord injury (SCI) suffering from pressure ulcers. Cytokines or their receptors, eg, interleukins IL-6 and IL-2, IL-2R (the soluble interleukin-2 receptor), and the intercellular adhesion molecule ICAM-1, are mediators of immune response, inflammatory processes, and tissue remodeling involving the skin and other organs. Activation of these immune effectors and their accumulation in tissue can be associated with pathological changes or healing, and elevated plasma concentrations can indirectly reflect the magnitude of immune activation. DESIGN Participants were consecutively enrolled in a controlled, gender-specific study of the relationship between circulating IL-1 beta, IL-2, IL-2R, and ICAM-1 and pressure ulcers in patients with chronic SCI. SETTING The department of medicine of a university-affiliated medical center and the spinal cord injury service at a Department of Veterans Affairs medical center. PATIENTS OR OTHER PARTICIPANTS Seventy men with longstanding SCI (19 with pressure ulcers). The mean age was 49 +/- 14 (range 25 to 74 years). Duration of SCI ranged between 1 and 46 years, and the level of injury varied from C2 to L5. The control group consisted of 20 healthy, able-bodied volunteers (10 men and 10 women aged 25 to 50 years). MAIN OUTCOME MEASURES Circulating plasma levels of IL-6, IL-2, IL-2R, and ICAM-1 and their relation to the rate of wound healing in subjects with SCI. RESULTS Plasma concentrations of bioactive molecules IL-6, IL-2R, and ICAM-1 were numerically or significantly elevated in all patients with SCI as compared to able-bodied individuals. The greatest increase in concentration was seen in those patients with pressure ulcers who demonstrated slow healing of their wounds. CONCLUSIONS SCI and trauma to insensitive tissue result in immunoactivation. In patients with SCI and pressure ulcers, elevated levels of circulating ICAM-1 and IL-2R may have diagnostic, prognostic, and therapeutic value in predicting or differentiating subgroups of patients who will vary in the severity or the rate of healing of their wounds.

4-Aminopyridine Improves Pulmonary Function in Quadriplegic Humans with Longstanding Spinal Cord Injury

Study Objective. To test the hypothesis that 4‐aminopyridine (4‐AP) might cause clinically evident improvement in pulmonary function in humans with chronic spinal cord injury (chronic SCI).

Heart rate variability is altered following spinal cord injury

Spinal cord injury (SCI) patients are know to suffer from autonomic failure as a result of their injury. The magnitude of the dysautonomia resulting from such an injury is difficult to predict or characterize and, in varying degree, it impedes the recovery of physiological homeostasis. This study is intended to investigate the effectiveness of heart rate variability (HRV) analysis as a method of quantifying and characterizing autonomic function in patients with traumatic spinal myelopathy. HRV analysis was carried out in 13 male SCI patients (six tetraplegic, seven paraplegic) and 13 age-matched, able-bodied controls. Twenty-four hour ambulatory and sleep ECG tracings were obtained. Time domain, amplitude, and power spectral analyses were used to study HRV and autonomic function. Both tetraplegic (20±12 ms, mean ±SD) and paraplegic (22±8 ms) subjects demonstrated significant loss of low frequency 24-hour HRV compared to able-bodied controls (36±14 ms, p<0.05) and during sleep. This was interpreted as being consistent with predominantly sympathetic denervation uninfluenced by degree of physical activity. There were no significant differences between groups in parasympathetically mediated high frequency HRV. We conclude that HRV analysis is capable of distinguishing between SCI or able-bodied humans and among tetraplegic and paraplegic patients. Patterns of altered HRV may be useful in more completely characterizing or stratifying changes in physiology associated with injury level and may have diagnostic, prognostic, or therapeutic significance.

4-Aminopyridine Alters Gait Characteristics and Enhances Locomotion in Spinal Cord Injured Humans

Recovery of useful motor function in humans with spinal cord injury (SCI) is a primary and elusive goal. In this preliminary study, we describe efforts to delineate the pharmacological effects of 4-aminopyridine (4-AP) on gait parameters in spinal cord injured humans who have retained some capacity to ambulate bipedally. A sequential entry, open label study was made of the effects of a single oral administration of an immediate-release formulation of 4-AP on the time-course profile of changes in component parameters of bipedal gait in ambulatory volunteers with chronic SCI. Nine healthy, rehabilitated, community-adapted male volunteers (six tetraparetic, three paraparetic), who sustained their injuries more than one year prior to entry into the study, ingested a single 10-mg dose of 4-aminopyridine after an overnight fast. Gait analysis parameters included velocity (meters/min), cadence (steps/min), stride length (meters), gait cycle (seconds), and double limb support (percent of gait cycle). They were measured for 24 hours using a sampling-rich strategy (nine duplicate measurements over 24 hrs). Repeated measures (randomized block) analysis of variance (ANOVA) and paired t-tests were used to test for the significance of differences between means and variances. The apparent pharmacological effect of 4-AP is associated with statistically significant changes in one or more of the component elements used to assess the characteristics and efficiency of bipedal gait. These changes in gait analysis parameters correspond temporally with the improvements in pulmonary function and heart rate variability previously described by us. 4-AP appears to enhance gait in a subset of humans with SCI. In this preliminary study we report, for the first time, an apparent effect of 4-AP on gait in spinal cord injured humans and suggest that the pharmacological effects of 4-AP may have clinically significant application in the restoration of useful motor function.

Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury

Fampridine SR (4‐aminopyridine) is a potassium channel‐blocking drug currently being investigated for its therapeutic efficacy in ameliorating central conduction deficits due to demyelination in patients with spinal cord injury (SCI). The present open‐label pharmacokinetic trial examined the absorption characteristics of a sustained‐release form of the drug in 25 SCI subjects with chronic in complete injuries. The overall group mean Cmax of 27.7 ± 6.2 ng/mL occurred at a tmsx of 3.4 ± 1.4 hours. AUC0–12 was 210.5 ± 49.5 ng/mL•h. For paraplegics, AUCtmax was 76.02 ± 33.28 and for tetraplegics was significantly less at 51.25 ± 20.36 (p = 0.037). A statistically significant difference in the initial rate and extent of absorption, but not in total 4‐AP bioavailability over the 12‐hour study period, was evident between tetraplegic patients, 0.60 ± 0.23, and paraplegic patients, 0.39 ± 0.14 (p = 0.02). There was a linear correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax. These results confirm and extend previous observations of different rates of drug absorption among SCI patients with lesions above and below the sympathetic outflow (T6) and provide evidence of the absorption characteristics of this sustained‐release form of 4‐aminopyridine, which is helpful for optimal dosing.

Decreased Systemic Clearance of Lorazepam in Humans With Spinal Cord Injury

Serum concentration‐time course profiles, serum protein binding, and disposition parameters of lorazepam (LRZ), a benzodiazepine with sedative‐hypnotic, anxiolytic, and antiseizure properties, were studied as part of a systematic effort to define population‐specific pharmacokinetic behavior in humans with chronic spinal cord injury (SCI). Twenty‐four healthy subjects (nine tetraplegic, six paraplegic, nine able‐bodied) were given an IV bolus of 2.0 mg of LRZ. Noncompartmental estimation of pharmacokinetic parameters disclosed a 37% decrease in the total systemic clearance (CL) of LRZ in tetraplegic patients. Altered LRZ clearance was observed independently of significant changes in volume of distribution or serum protein binding. The early elimination of LRZ (0–10 hr) was characterized by wide fluctuations in serum concentration suggestive of impaired enterohepatic circulation and could be distinguished from LRZ elimination observed in able‐bodied subjects. We conclude that decreased systemic CL and the altered terminal elimination profile of LRZ are attributable to the pathophysiology of SCI.

Effects of Chronic Spinal Cord Injury and Pressure Ulcer on 25(OH)-Vitamin D Levels

We studied 92 spinal cord injured (SCI) men (50 paraplegics and 42 quadriplegics) with normal renal function, 38 of whom had single or multiple pressure ulcers. The results were compared with those of 28 able-bodied normal controls. Serum concentrations of calcium and magnesium were measured by atomic absorption spectrometry, and 25(OH)-vitamin D was quantitated by a specific competitive binding assay using a sensitive vitamin D binding protein and tritiated 25(OH)-vitamin D. The SCI group exhibited significant reductions in serum 25(OH)-vitamin D and total calcium concentrations as compared to the normal control group. Although the mean serum concentration of 25(OH)-vitamin D in the quadriplegic patients as a whole was lower than that found in the entire paraplegic group, the difference did not attain statistical significance. Similar observations were made when the ulcer-free subgroups of paraplegics and quadriplegics were compared. The SCI subgroup which was least physically active, i.e., those with pressure ulcers, showed the greatest depression of serum 25(OH)-vitamin D, calcium, and magnesium concentrations. The observed reduction in serum 25(OH)-vitamin D in SCI patients appears to be partly related to reduced cutaneous vitamin D biosynthesis from sunlight deprivation occasioned by physical disability and hospitalization. In addition, nutritional deficiency and altered intestinal transport may be involved. The reduction in serum calcium concentration may be related to abnormal vitamin D metabolism and hypoalbuminemia (reduced protein-bound calcium).

Amikacin Pharmacokinetics in Patients with Spinal Cord Injury

The influence of chronic (> 1 yr duration) spinal cord injury (SCI) on the disposition of amikacin was studied in seven healthy subjects with SCI (five paraplegic, two tetraplegic) and seven able‐bodied controls (intact neuraxes). The time course of amikacin serum concentration after a 30‐minute infusion (7.5 mg/kg) was followed for up to 8.5 hours using fluorescence polarization immunoassay. Pharmacokinetic values were estimated by a noncompartmental analysis (NC). Amikacin steady‐state volume of distribution (Vss) was increased to 0.20 ± 0.04 l/kg (mean ± SD) as compared to 0.17 ± 0.02 l/kg in able‐bodied controls (p 0.03), and its mean terminal elimination half‐life in patients with SCI was prolonged by 0.64 hours over the control value of 2.11 ± 0.27 hours (p 0.01). The NC estimated mean residence time (MRT) in patients with SCI (3.65 ± 0.75 hrs) was 0.89 hours longer than that observed in controls (p 0.03). Our data suggest that the Vss, half‐life, and MRT of amikacin are increased in persons with chronic SCI. As a result, amikacin dosing regimens developed in able‐bodied humans may demonstrate diminished efficacy when extrapolated uncritically to these patients.

4-aminopyridine influences heart rate variability in long-standing spinal cord injury.

Humans with traumatic spinal myelopathy exhibit intralesional conduction block and autonomic failure as pathophysiologic sequelae of their injury. Analysis of heart rate variability (HRV) provides a means of assessing changes in the function of the autonomic nervous system (ANS) and the cardiac sequelae of injury. Thirteen patients with long-standing spinal cord injury (SCI) and 13 able-bodied controls were studied. Each patient received a single 10-mg dose of an immediate release (IR) formulation of 4-aminopyridine (4-AP). Twenty-four hour heart rate (HR) and HRV data were acquired using a Holter ambulatory electrocardiographic (ECG) monitor. Analysis of acquired data was carried out using a minicomputer programmed to separate ECG R-R intervals into frequency patterns that appear as peaks dispersed along a frequency range of 0.0 to 1.0 Hz. Twenty-four hour baseline, pretreatment low-frequency (LF) HRV power was diminished in all patients with SCI compared with able-bodied-controls and was significantly decreased in tetraplegic patients (P = 0.03). This difference in LF HRV power disappeared during the 24 hours immediately after administration of 4-AP, and mean LF HRV power in tetraplegic patients became indistinguishable from LF HRV power in controls. 4-Aminopyridine appears to influence ANS function and LF HRV in humans with long-standing SCI.