Jack L. Segal

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).

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.

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.

Bioelectrical Impedance Analysis as an Assessment of Diuresis in Congestive Heart Failure

Objective: To compare changes in bioimpedance parameters and calculated total body water (TBW) with conventional measurements used to assess the efficacy of diuretic therapy in the treatment of heart failure. Setting: A Veterans Affairs tertiary care, teaching hospital. Subjects: Twelve patients with New York Heart Association (NYHA) class HI congestive heart failure (CHF). Design: Prospective, consecutive sample, cohort, open label. Interventions: Parenterally administered furosemide; clinically dictated, outcome-oriented, adjunctive therapy of CHF. Outcomes: Bioelectrical impedance analysis (BIA) parameters, measured volume of diuresis and changes in body weight, defined clinical endpoints (NYHA criteria). Results: Three days of diuretic therapy with furosemide (oral and/or intravenous) for CHF was associated with a measured weight loss of 4.1 ± 0.6 kg and statistically significant increases in resistance and reactance of 20.8% ± 2.7% and 22.7% ± 6.1%, respectively (p < 0.005). Calculated TBW using BIA parameters and standard equations decreased on average by 6.1 ± 0.6 L or 11.2% ± 1.1% (p < 0.001). A significant inverse correlation was observed between change in measured body weight and total body reactance (p = 0.02). Conclusions: Single-frequency BIA appears to have limited clinical usefulness as a method of assessing diuretic therapy in the management of CHF. Its greatest usefulness appears to lie in the assessment of serial changes in individual patients and patient populations that are physiologically or metabolically homogeneous. Further studies are needed to establish the validity of BIA in patients with decompensated CHF.

Metoclopramide increases the bioavailability of dantrolene in spinal cord injury.

A study was conducted to determine the effect of metoclopramide on the disposition of dantrolene in patients with spinal cord injury (SCI) and in neurologically intact, able‐bodied volunteers. Fifteen serum samples each were collected from 6 able‐bodied volunteers and 13 patients with SCI (7 paraplegics, 6 quadriplegics) in a prospective, open‐label, pharmacokinetic study of a single 100‐mg oral dose of dantrolene. After a washout period, a single 10‐mg intravenous dose of metoclopramide was given along with dantrolene to the patients with SCI only, and the study was repeated in sequential, crossover fashion. Concentrations of dantrolene were measured by a high‐performance liquid chromatography (HPLC) assay. Numerical integration was used to calculate area under the curve (AUC) and mean residence time (MRT). Differences were studied using paired and two‐sample, nonparametric tests, with 0.05 as the significance level. Without metoclopramide, the AUC of dantrolene was larger in able‐bodied volunteers than in patients with SCI, and the MRT of dantrolene was similar both groups. When patients with SCI received metoclopramide before treatment with dantrolene, the median increase in the AUC for dantrolene was 57%, with no change in MRT. This pharmacokinetic interaction is probably attributable to augmented absorption and could alter the pharmacologic action of dantrolene. Concurrent treatment of patients with SCI with metoclopramide and dantrolene should be accompanied by careful surveillance to avoid toxicity and preserve efficacy.

Circulating Levels of Soluble Interleukin 2 Receptors Are Elevated in the Sera of Humans with Spinal Cord Injury

A unique molecular regulatory mechanism or final common molecular pathway mediating the autonomic dysfunction and several pathobiologic sequelae of spinal cord injury (SCI) in humans has not been delineated. Although seemingly disparate in etiopathogenesis, much of the pathology caused by traumatic disruption of the spinal cord may be attributable to the pleiotropism demonstrated by a unique family of endogenous bioactive molecules, the interleukins. To begin testing this hypothesis, we examined the sera of patients with chronic SCI for elevations in interleukin 1 beta (IL-1 beta) and interleukin 2 receptor (IL-2R) and compared them to a control population of able-bodied subjects. In comparison to control subjects, a statistically significant increase in IL-2R was observed in patients with cervical spinal myelopathy. Elevated levels of IL-2R were not seen in paraplegic patients. Significant differences between the means and variances of serum IL-1 beta could not be detected among the study groups. We conclude that the sera of quadriplegic patients with chronic SCI contain elevated levels of IL-2R and suggest that the elevated levels of IL-2R may be of diagnostic, prognostic, and therapeutic importance.